CINXE.COM

<!DOCTYPE html> <html lang="en" class="grade-c"> <head> <title>Chemical logic of MraY inhibition by antibacterial nucleoside natural products | Nature Communications</title> <link rel="alternate" type="application/rss+xml" href="https://www.nature.com/ncomms.rss"/> <script id="save-data-connection-testing"> function hasConnection() { return navigator.connection || navigator.mozConnection || navigator.webkitConnection || navigator.msConnection; } function createLink(src) { var preloadLink = document.createElement("link"); preloadLink.rel = "preload"; preloadLink.href = src; preloadLink.as = "font"; preloadLink.type = "font/woff2"; preloadLink.crossOrigin = ""; document.head.insertBefore(preloadLink, document.head.firstChild); } var connectionDetail = { saveDataEnabled: false, slowConnection: false }; var connection = hasConnection(); if (connection) { connectionDetail.saveDataEnabled = connection.saveData; if (/\slow-2g|2g/.test(connection.effectiveType)) { connectionDetail.slowConnection = true; } } if (!(connectionDetail.saveDataEnabled || connectionDetail.slowConnection)) { createLink("/static/fonts/HardingText-Regular-Web-cecd90984f.woff2"); } else { document.documentElement.classList.add('save-data'); } </script> <link rel="preconnect" href="https://cmp.nature.com" crossorigin> <meta http-equiv="X-UA-Compatible" content="IE=edge"> <meta name="applicable-device" content="pc,mobile"> <meta name="viewport" content="width=device-width,initial-scale=1.0,maximum-scale=5,user-scalable=yes"> <meta name="360-site-verification" content="5a2dc4ab3fcb9b0393241ffbbb490480" /> <script data-test="dataLayer"> window.dataLayer = [{"content":{"category":{"contentType":"article","legacy":{"webtrendsPrimaryArticleType":"research","webtrendsSubjectTerms":"antibiotics;transferases;x-ray-crystallography","webtrendsContentCategory":null,"webtrendsContentCollection":null,"webtrendsContentGroup":"Nature Communications","webtrendsContentGroupType":null,"webtrendsContentSubGroup":"Article","status":null}},"article":{"doi":"10.1038/s41467-019-10957-9"},"attributes":{"cms":null,"deliveryPlatform":"oscar","copyright":{"open":true,"legacy":{"webtrendsLicenceType":"http://creativecommons.org/licenses/by/4.0/"}}},"contentInfo":{"authors":["Ellene H. Mashalidis","Benjamin Kaeser","Yuma Terasawa","Akira Katsuyama","Do-Yeon Kwon","Kiyoun Lee","Jiyong Hong","Satoshi Ichikawa","Seok-Yong Lee"],"publishedAt":1562025600,"publishedAtString":"2019-07-02","title":"Chemical logic of MraY inhibition by antibacterial nucleoside natural products","legacy":null,"publishedAtTime":null,"documentType":"aplusplus","subjects":"Antibiotics,Transferases,X-ray crystallography"},"journal":{"pcode":"ncomms","title":"nature communications","volume":"10","issue":"1","id":41467,"publishingModel":"Open Access"},"authorization":{"status":true},"features":[{"name":"furtherReadingSection","present":true}],"collection":null},"page":{"category":{"pageType":"article"},"attributes":{"template":"mosaic","featureFlags":[{"name":"nature-onwards-journey","active":false}],"testGroup":null},"search":null},"privacy":{},"version":"1.0.0","product":null,"session":null,"user":null,"backHalfContent":true,"country":"HK","hasBody":true,"uneditedManuscript":false,"twitterId":["o3xnx","o43y9","o3ef7"],"baiduId":"d38bce82bcb44717ccc29a90c4b781ea","japan":false}]; window.dataLayer.push({ ga4MeasurementId: 'G-ERRNTNZ807', ga360TrackingId: 'UA-71668177-1', twitterId: ['3xnx', 'o43y9', 'o3ef7'], baiduId: 'd38bce82bcb44717ccc29a90c4b781ea', ga4ServerUrl: 'https://collect.nature.com', imprint: 'nature' }); </script> <script> (function(w, d) { w.config = w.config || {}; w.config.mustardcut = false; if (w.matchMedia && w.matchMedia('only print, only all and (prefers-color-scheme: no-preference), only all and (prefers-color-scheme: light), only all and (prefers-color-scheme: dark)').matches) { w.config.mustardcut = true; d.classList.add('js'); d.classList.remove('grade-c'); d.classList.remove('no-js'); } })(window, document.documentElement); </script> <style>@media only print, only all and (prefers-color-scheme: no-preference), only all and (prefers-color-scheme: light), only all and (prefers-color-scheme: dark) { .c-article-editorial-summary__container .c-article-editorial-summary__article-title,.c-card--major .c-card__title,.c-card__title,.u-h2,.u-h3,h2,h3{-webkit-font-smoothing:antialiased;font-family:Harding,Palatino,serif;font-weight:700;letter-spacing:-.0117156rem}.c-article-editorial-summary__container .c-article-editorial-summary__article-title,.c-card__title,.u-h3,h3{font-size:1.25rem;line-height:1.4rem}.c-reading-companion__figure-title,.u-h4,h4{-webkit-font-smoothing:antialiased;font-weight:700;line-height:1.4rem}html{text-size-adjust:100%;box-sizing:border-box;font-size:100%;height:100%;line-height:1.15;overflow-y:scroll}body{background:#eee;color:#222;font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif;font-size:1.125rem;line-height:1.76;margin:0;min-height:100%}details,main{display:block}h1{font-size:2em;margin:.67em 0}a,sup{vertical-align:baseline}a{background-color:transparent;color:#069;overflow-wrap:break-word;text-decoration:underline;text-decoration-skip-ink:auto;word-break:break-word}b{font-weight:bolder}sup{font-size:75%;line-height:0;position:relative;top:-.5em}img{border:0;height:auto;max-width:100%;vertical-align:middle}button,input,select{font-family:inherit;font-size:100%;line-height:1.15;margin:0}button,input{overflow:visible}button,select{text-transform:none}[type=submit],button{-webkit-appearance:button}[type=checkbox]{box-sizing:border-box;padding:0}summary{display:list-item}[hidden]{display:none}button{border-radius:0;cursor:pointer;font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif}h1{-webkit-font-smoothing:antialiased;font-family:Harding,Palatino,serif;font-size:2rem;font-weight:700;letter-spacing:-.0390625rem;line-height:2.25rem}.c-card--major .c-card__title,.u-h2,.u-h3,h2{font-family:Harding,Palatino,serif;letter-spacing:-.0117156rem}.c-card--major .c-card__title,.u-h2,h2{-webkit-font-smoothing:antialiased;font-size:1.5rem;font-weight:700;line-height:1.6rem}.u-h3{font-size:1.25rem}.c-card__title,.c-reading-companion__figure-title,.u-h3,.u-h4,h4,h5,h6{-webkit-font-smoothing:antialiased;font-weight:700;line-height:1.4rem}.c-article-editorial-summary__container .c-article-editorial-summary__article-title,.c-card__title,h3{font-family:Harding,Palatino,serif;font-size:1.25rem}.c-article-editorial-summary__container .c-article-editorial-summary__article-title,h3{-webkit-font-smoothing:antialiased;font-weight:700;letter-spacing:-.0117156rem;line-height:1.4rem}.c-reading-companion__figure-title,.u-h4,h4{font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif;font-size:1.125rem;letter-spacing:-.0117156rem}button:focus{outline:3px solid #fece3e;will-change:transform}input+label{padding-left:.5em}nav ol,nav ul{list-style:none none}p:empty{display:none}.sans-serif{font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif}.article-page{background:#fff}.c-article-header{font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif;margin-bottom:40px}.c-article-identifiers{color:#6f6f6f;display:flex;flex-wrap:wrap;font-size:1rem;line-height:1.3;list-style:none;margin:0 0 8px;padding:0}.c-article-identifiers__item{border-right:1px solid #6f6f6f;list-style:none;margin-right:8px;padding-right:8px}.c-article-identifiers__item:last-child{border-right:0;margin-right:0;padding-right:0}.c-article-title{font-size:1.5rem;line-height:1.25;margin:0 0 16px}@media only screen and (min-width:768px){.c-article-title{font-size:1.875rem;line-height:1.2}}.c-article-author-list{display:inline;font-size:1rem;list-style:none;margin:0 8px 0 0;padding:0;width:100%}.c-article-author-list__item{display:inline;padding-right:0}.c-article-author-list svg{margin-left:4px}.c-article-author-list__show-more{display:none;margin-right:4px}.c-article-author-list__button,.js .c-article-author-list__item--hide,.js .c-article-author-list__show-more{display:none}.js .c-article-author-list--long .c-article-author-list__show-more,.js .c-article-author-list--long+.c-article-author-list__button{display:inline}@media only screen and (max-width:539px){.js .c-article-author-list__item--hide-small-screen{display:none}.js .c-article-author-list--short .c-article-author-list__show-more,.js .c-article-author-list--short+.c-article-author-list__button{display:inline}}#uptodate-client,.js .c-article-author-list--expanded .c-article-author-list__show-more{display:none!important}.js .c-article-author-list--expanded .c-article-author-list__item--hide-small-screen{display:inline!important}.c-article-author-list__button,.c-button-author-list{background:#ebf1f5;border:4px solid #ebf1f5;border-radius:20px;color:#666;font-size:.875rem;line-height:1.4;padding:2px 11px 2px 8px;text-decoration:none}.c-article-author-list__button svg,.c-button-author-list svg{margin:1px 4px 0 0}.c-article-author-list__button:hover,.c-button-author-list:hover{background:#069;border-color:transparent;color:#fff}.c-article-info-details{font-size:1rem;margin-bottom:8px;margin-top:16px}.c-article-info-details__cite-as{border-left:1px solid #6f6f6f;margin-left:8px;padding-left:8px}.c-article-metrics-bar{display:flex;flex-wrap:wrap;font-size:1rem;line-height:1.3}.c-article-metrics-bar__wrapper{margin:16px 0}.c-article-metrics-bar__item{align-items:baseline;border-right:1px solid #6f6f6f;margin-right:8px}.c-article-metrics-bar__item:last-child{border-right:0}.c-article-metrics-bar__count{font-weight:700;margin:0}.c-article-metrics-bar__label{color:#626262;font-style:normal;font-weight:400;margin:0 10px 0 5px}.c-article-metrics-bar__details{margin:0}.c-article-main-column{font-family:Harding,Palatino,serif;margin-right:8.6%;width:60.2%}@media only screen and (max-width:1023px){.c-article-main-column{margin-right:0;width:100%}}.c-article-extras{float:left;font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif;width:31.2%}@media only screen and (max-width:1023px){.c-article-extras{display:none}}.c-article-associated-content__container .c-article-associated-content__title,.c-article-section__title{border-bottom:2px solid #d5d5d5;font-size:1.25rem;margin:0;padding-bottom:8px}@media only screen and (min-width:768px){.c-article-associated-content__container .c-article-associated-content__title,.c-article-section__title{font-size:1.5rem;line-height:1.24}}.c-article-associated-content__container .c-article-associated-content__title{margin-bottom:8px}.c-article-body p{margin-bottom:24px;margin-top:0}.c-article-section{clear:both}.c-article-section__content{margin-bottom:40px;padding-top:8px}@media only screen and (max-width:1023px){.c-article-section__content{padding-left:0}}.c-article-authors-search{margin-bottom:24px;margin-top:0}.c-article-authors-search__item,.c-article-authors-search__title{font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif}.c-article-authors-search__title{color:#626262;font-size:1.05rem;font-weight:700;margin:0;padding:0}.c-article-authors-search__item{font-size:1rem}.c-article-authors-search__text{margin:0}.c-article-license__badge,c-card__section{margin-top:8px}.c-code-block{border:1px solid #eee;font-family:monospace;margin:0 0 24px;padding:20px}.c-code-block__heading{font-weight:400;margin-bottom:16px}.c-code-block__line{display:block;overflow-wrap:break-word;white-space:pre-wrap}.c-article-share-box__no-sharelink-info{font-size:.813rem;font-weight:700;margin-bottom:24px;padding-top:4px}.c-article-share-box__only-read-input{border:1px solid #d5d5d5;box-sizing:content-box;display:inline-block;font-size:.875rem;font-weight:700;height:24px;margin-bottom:8px;padding:8px 10px}.c-article-share-box__button--link-like{background-color:transparent;border:0;color:#069;cursor:pointer;font-size:.875rem;margin-bottom:8px;margin-left:10px}.c-article-editorial-summary__container{font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif;font-size:1rem}.c-article-editorial-summary__container .c-article-editorial-summary__content p:last-child{margin-bottom:0}.c-article-editorial-summary__container .c-article-editorial-summary__content--less{max-height:9.5rem;overflow:hidden}.c-article-editorial-summary__container .c-article-editorial-summary__button{background-color:#fff;border:0;color:#069;font-size:.875rem;margin-bottom:16px}.c-article-editorial-summary__container .c-article-editorial-summary__button.active,.c-article-editorial-summary__container .c-article-editorial-summary__button.hover,.c-article-editorial-summary__container .c-article-editorial-summary__button:active,.c-article-editorial-summary__container .c-article-editorial-summary__button:hover{text-decoration:underline;text-decoration-skip-ink:auto}.c-article-associated-content__container .c-article-associated-content__collection-label{font-size:.875rem;line-height:1.4}.c-article-associated-content__container .c-article-associated-content__collection-title{line-height:1.3}.c-context-bar{box-shadow:0 0 10px 0 rgba(51,51,51,.2);position:relative;width:100%}.c-context-bar__title{display:none}.c-reading-companion{clear:both;min-height:389px}.c-reading-companion__sticky{max-width:389px}.c-reading-companion__scroll-pane{margin:0;min-height:200px;overflow:hidden auto}.c-reading-companion__tabs{display:flex;flex-flow:row nowrap;font-size:1rem;list-style:none;margin:0 0 8px;padding:0}.c-reading-companion__tabs>li{flex-grow:1}.c-reading-companion__tab{background-color:#eee;border:1px solid #d5d5d5;border-image:initial;border-left-width:0;color:#069;font-size:1rem;padding:8px 8px 8px 15px;text-align:left;width:100%}.c-reading-companion__tabs li:first-child .c-reading-companion__tab{border-left-width:1px}.c-reading-companion__tab--active{background-color:#fff;border-bottom:1px solid #fff;color:#222;font-weight:700}.c-reading-companion__sections-list{list-style:none;padding:0}.c-reading-companion__figures-list,.c-reading-companion__references-list{list-style:none;min-height:389px;padding:0}.c-reading-companion__references-list--numeric{list-style:decimal inside}.c-reading-companion__sections-list{margin:0 0 8px;min-height:50px}.c-reading-companion__section-item{font-size:1rem;padding:0}.c-reading-companion__section-item a{display:block;line-height:1.5;overflow:hidden;padding:8px 0 8px 16px;text-overflow:ellipsis;white-space:nowrap}.c-reading-companion__figure-item{border-top:1px solid #d5d5d5;font-size:1rem;padding:16px 8px 16px 0}.c-reading-companion__figure-item:first-child{border-top:none;padding-top:8px}.c-reading-companion__reference-item{border-top:1px solid #d5d5d5;font-size:1rem;padding:8px 8px 8px 16px}.c-reading-companion__reference-item:first-child{border-top:none}.c-reading-companion__reference-item a{word-break:break-word}.c-reading-companion__reference-citation{display:inline}.c-reading-companion__reference-links{font-size:.813rem;font-weight:700;list-style:none;margin:8px 0 0;padding:0;text-align:right}.c-reading-companion__reference-links>a{display:inline-block;padding-left:8px}.c-reading-companion__reference-links>a:first-child{display:inline-block;padding-left:0}.c-reading-companion__figure-title{display:block;margin:0 0 8px}.c-reading-companion__figure-links{display:flex;justify-content:space-between;margin:8px 0 0}.c-reading-companion__figure-links>a{align-items:center;display:flex}.c-reading-companion__figure-full-link svg{height:.8em;margin-left:2px}.c-reading-companion__panel{border-top:none;display:none;margin-top:0;padding-top:0}.c-cod,.c-reading-companion__panel--active{display:block}.c-cod{font-size:1rem;width:100%}.c-cod__form{background:#ebf0f3}.c-cod__prompt{font-size:1.125rem;line-height:1.3;margin:0 0 24px}.c-cod__label{display:block;margin:0 0 4px}.c-cod__row{display:flex;margin:0 0 16px}.c-cod__row:last-child{margin:0}.c-cod__input{border:1px solid #d5d5d5;border-radius:2px;flex-basis:75%;flex-shrink:0;margin:0;padding:13px}.c-cod__input--submit{background-color:#069;border:1px solid #069;color:#fff;flex-shrink:1;margin-left:8px;transition:background-color .2s ease-out 0s,color .2s ease-out 0s}.c-cod__input--submit-single{flex-basis:100%;flex-shrink:0;margin:0}.c-cod__input--submit:focus,.c-cod__input--submit:hover{background-color:#fff;color:#069}.c-pdf-download__link .u-icon{padding-top:2px}.c-pdf-download{display:flex;margin-bottom:16px;max-height:48px}@media only screen and (min-width:540px){.c-pdf-download{max-height:none}}@media only screen and (min-width:1024px){.c-pdf-download{max-height:48px}}.c-pdf-download__link{display:flex;flex:1 1 0%}.c-pdf-download__link:hover{text-decoration:none}.c-pdf-download__text{padding-right:4px}@media only screen and (max-width:539px){.c-pdf-download__text{text-transform:capitalize}}@media only screen and (min-width:540px){.c-pdf-download__text{padding-right:8px}}.c-context-bar--sticky .c-pdf-download{display:block;margin-bottom:0;white-space:nowrap}@media only screen and (max-width:539px){.c-pdf-download .u-sticky-visually-hidden{clip:rect(0,0,0,0);border:0;height:1px;margin:-100%;overflow:hidden;padding:0;position:absolute!important;width:1px}}.c-pdf-container{display:flex;justify-content:flex-end}@media only screen and (max-width:539px){.c-pdf-container .c-pdf-download{display:flex;flex-basis:100%}}.c-pdf-container .c-pdf-download+.c-pdf-download{margin-left:16px}.c-article-extras .c-pdf-container .c-pdf-download{width:100%}.c-article-extras .c-pdf-container .c-pdf-download+.c-pdf-download{margin-left:0}@media only screen and (min-width:540px){.c-context-bar--sticky .c-pdf-download__link{align-items:center;flex:1 1 183px}}@media only screen and (max-width:320px){.c-context-bar--sticky .c-pdf-download__link{padding:16px}}.article-page--commercial .c-article-main-column .c-pdf-button__container .c-pdf-download{display:none}@media only screen and (max-width:1023px){.article-page--commercial .c-article-main-column .c-pdf-button__container .c-pdf-download{display:block}}.c-status-message--success{border-bottom:2px solid #00b8b0;justify-content:center;margin-bottom:16px;padding-bottom:8px}.c-recommendations-list__item .c-card{flex-basis:100%}.c-recommendations-list__item .c-card__image{align-items:baseline;flex:1 1 40%;margin:0 0 0 16px;max-width:150px}.c-recommendations-list__item .c-card__image img{border:1px solid #cedbe0;height:auto;min-height:0;position:static}@media only screen and (max-width:1023px){.c-recommendations-list__item .c-card__image{display:none}}.c-card__layout{display:flex;flex:1 1 auto;justify-content:space-between}.c-card__title-recommendation{-webkit-box-orient:vertical;-webkit-line-clamp:4;display:-webkit-box;font-size:1rem;font-weight:700;line-height:1.4;margin:0 0 8px;max-height:5.6em;overflow:hidden!important;text-overflow:ellipsis}.c-card__title-recommendation .c-card__link{color:inherit}.c-card__title-recommendation .c-card__link:hover{text-decoration:underline}.c-card__title-recommendation .MathJax_Display{display:inline!important}.c-card__link:not(.c-card__link--no-block-link):before{z-index:1}.c-article-metrics__heading a,.c-article-metrics__posts .c-card__title a,.c-article-recommendations-card__link{color:inherit}.c-recommendations-column-switch .c-meta{margin-top:auto}.c-article-recommendations-card__meta-type,.c-meta .c-meta__item:first-child{font-weight:700}.c-article-body .c-article-recommendations-card__authors{display:none;font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif;font-size:.875rem;line-height:1.5;margin:0 0 8px}@media only screen and (max-width:539px){.c-article-body .c-article-recommendations-card__authors{display:block;margin:0}}.c-article-metrics__posts .c-card__title{font-size:1.05rem}.c-article-metrics__posts .c-card__title+span{color:#6f6f6f;font-size:1rem}p{overflow-wrap:break-word;word-break:break-word}.c-ad{text-align:center}@media only screen and (min-width:320px){.c-ad{padding:8px}}.c-ad--728x90{background-color:#ccc;display:none}.c-ad--728x90 .c-ad__inner{min-height:calc(1.5em + 94px)}@media only screen and (min-width:768px){.js .c-ad--728x90{display:none}}.c-ad__label{color:#333;font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif;font-size:.875rem;font-weight:400;line-height:1.5;margin-bottom:4px}.c-author-list{color:#6f6f6f;font-family:inherit;font-size:1rem;line-height:inherit;list-style:none;margin:0;padding:0}.c-author-list>li,.c-breadcrumbs>li,.c-footer__links>li,.js .c-author-list,.u-list-comma-separated>li,.u-list-inline>li{display:inline}.c-author-list>li:not(:first-child):not(:last-child):before{content:", "}.c-author-list>li:not(:only-child):last-child:before{content:" & "}.c-author-list--compact{font-size:.875rem;line-height:1.4}.c-author-list--truncated>li:not(:only-child):last-child:before{content:" ... "}.js .c-author-list__hide{display:none;visibility:hidden}.js .c-author-list__hide:first-child+*{margin-block-start:0}.c-meta{color:inherit;font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif;font-size:.875rem;line-height:1.4;list-style:none;margin:0;padding:0}.c-meta--large{font-size:1rem}.c-meta--large .c-meta__item{margin-bottom:8px}.c-meta__item{display:inline-block;margin-bottom:4px}.c-meta__item:not(:last-child){border-right:1px solid #d5d5d5;margin-right:4px;padding-right:4px}@media only screen and (max-width:539px){.c-meta__item--block-sm-max{display:block}.c-meta__item--block-sm-max:not(:last-child){border-right:none;margin-right:0;padding-right:0}}@media only screen and (min-width:1024px){.c-meta__item--block-at-lg{display:block}.c-meta__item--block-at-lg:not(:last-child){border-right:none;margin-right:0;padding-right:0}}.c-meta__type{font-weight:700;text-transform:none}.c-skip-link{background:#069;bottom:auto;color:#fff;font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif;font-size:.875rem;padding:8px;position:absolute;text-align:center;transform:translateY(-100%);z-index:9999}@media (prefers-reduced-motion:reduce){.c-skip-link{transition:top .3s ease-in-out 0s}}@media print{.c-skip-link{display:none}}.c-skip-link:link{color:#fff}.c-status-message{align-items:center;box-sizing:border-box;display:flex;font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif;font-size:1rem;position:relative;width:100%}.c-card__summary>p:last-child,.c-status-message :last-child{margin-bottom:0}.c-status-message--boxed{background-color:#fff;border:1px solid #eee;border-radius:2px;line-height:1.4;padding:16px}.c-status-message__heading{font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif;font-size:1rem;font-weight:700}.c-status-message__icon{fill:currentcolor;display:inline-block;flex:0 0 auto;height:1.5em;margin-right:8px;transform:translate(0);vertical-align:text-top;width:1.5em}.c-status-message__icon--top{align-self:flex-start}.c-status-message--info .c-status-message__icon{color:#003f8d}.c-status-message--boxed.c-status-message--info{border-bottom:4px solid #003f8d}.c-status-message--error .c-status-message__icon{color:#c40606}.c-status-message--boxed.c-status-message--error{border-bottom:4px solid #c40606}.c-status-message--success .c-status-message__icon{color:#00b8b0}.c-status-message--boxed.c-status-message--success{border-bottom:4px solid #00b8b0}.c-status-message--warning .c-status-message__icon{color:#edbc53}.c-status-message--boxed.c-status-message--warning{border-bottom:4px solid #edbc53}.c-breadcrumbs{color:#000;font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif;font-size:1rem;list-style:none;margin:0;padding:0}.c-breadcrumbs__link{color:#666}svg.c-breadcrumbs__chevron{fill:#888;height:10px;margin:4px 4px 0;width:10px}@media only screen and (max-width:539px){.c-breadcrumbs .c-breadcrumbs__item{display:none}.c-breadcrumbs .c-breadcrumbs__item:last-child,.c-breadcrumbs .c-breadcrumbs__item:nth-last-child(2){display:inline}}.c-card{background-color:transparent;border:0;box-shadow:none;display:flex;flex-direction:column;font-size:14px;min-width:0;overflow:hidden;padding:0;position:relative}.c-card--no-shape{background:0 0;border:0;box-shadow:none}.c-card__image{display:flex;justify-content:center;overflow:hidden;padding-bottom:56.25%;position:relative}@supports (aspect-ratio:1/1){.c-card__image{padding-bottom:0}}.c-card__image img{left:0;min-height:100%;min-width:100%;position:absolute}@supports ((-o-object-fit:cover) or (object-fit:cover)){.c-card__image img{height:100%;object-fit:cover;width:100%}}.c-card__body{flex:1 1 auto;padding:16px}.c-card--no-shape .c-card__body{padding:0}.c-card--no-shape .c-card__body:not(:first-child){padding-top:16px}.c-card__title{letter-spacing:-.01875rem;margin-bottom:8px;margin-top:0}[lang=de] .c-card__title{hyphens:auto}.c-card__summary{line-height:1.4}.c-card__summary>p{margin-bottom:5px}.c-card__summary a{text-decoration:underline}.c-card__link:not(.c-card__link--no-block-link):before{bottom:0;content:"";left:0;position:absolute;right:0;top:0}.c-card--flush .c-card__body{padding:0}.c-card--major{font-size:1rem}.c-card--dark{background-color:#29303c;border-width:0;color:#e3e4e5}.c-card--dark .c-card__title{color:#fff}.c-card--dark .c-card__link,.c-card--dark .c-card__summary a{color:inherit}.c-header{background-color:#fff;border-bottom:5px solid #000;font-size:1rem;line-height:1.4;margin-bottom:16px}.c-header__row{padding:0;position:relative}.c-header__row:not(:last-child){border-bottom:1px solid #eee}.c-header__split{align-items:center;display:flex;justify-content:space-between}.c-header__logo-container{flex:1 1 0px;line-height:0;margin:8px 24px 8px 0}.c-header__logo{transform:translateZ(0)}.c-header__logo img{max-height:32px}.c-header__container{margin:0 auto;max-width:1280px}.c-header__menu{align-items:center;display:flex;flex:0 1 auto;flex-wrap:wrap;font-weight:700;gap:8px 8px;line-height:1.4;list-style:none;margin:0 -8px;padding:0}@media print{.c-header__menu{display:none}}@media only screen and (max-width:1023px){.c-header__menu--hide-lg-max{display:none;visibility:hidden}}.c-header__menu--global{font-weight:400;justify-content:flex-end}.c-header__menu--global svg{display:none;visibility:hidden}.c-header__menu--global svg:first-child+*{margin-block-start:0}@media only screen and (min-width:540px){.c-header__menu--global svg{display:block;visibility:visible}}.c-header__menu--journal{font-size:.875rem;margin:8px 0 8px -8px}@media only screen and (min-width:540px){.c-header__menu--journal{flex-wrap:nowrap;font-size:1rem}}.c-header__item{padding-bottom:0;padding-top:0;position:static}.c-header__item--pipe{border-left:2px solid #eee;padding-left:8px}.c-header__item--padding{padding-bottom:8px;padding-top:8px}@media only screen and (min-width:540px){.c-header__item--dropdown-menu{position:relative}}@media only screen and (min-width:1024px){.c-header__item--hide-lg{display:none;visibility:hidden}}@media only screen and (max-width:767px){.c-header__item--hide-md-max{display:none;visibility:hidden}.c-header__item--hide-md-max:first-child+*{margin-block-start:0}}.c-header__link{align-items:center;color:inherit;display:inline-flex;gap:4px 4px;padding:8px;white-space:nowrap}.c-header__link svg{transition-duration:.2s}.c-header__show-text{display:none;visibility:hidden}.has-tethered .c-header__heading--js-hide:first-child+*{margin-block-start:0}@media only screen and (min-width:540px){.c-header__show-text{display:inline;visibility:visible}}.c-header__dropdown{background-color:#000;border-bottom:1px solid #2f2f2f;color:#eee;font-size:.875rem;line-height:1.2;padding:16px 0}@media print{.c-header__dropdown{display:none}}.c-header__heading{display:inline-block;font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif;font-size:1.25rem;font-weight:400;line-height:1.4;margin-bottom:8px}.c-header__heading--keyline{border-top:1px solid;border-color:#2f2f2f;margin-top:16px;padding-top:16px;width:100%}.c-header__list{display:flex;flex-wrap:wrap;gap:0 16px;list-style:none;margin:0 -8px}.c-header__flush{margin:0 -8px}.c-header__visually-hidden{clip:rect(0,0,0,0);border:0;height:1px;margin:-100%;overflow:hidden;padding:0;position:absolute!important;width:1px}.c-header__search-form{margin-bottom:8px}.c-header__search-layout{display:flex;flex-wrap:wrap;gap:16px 16px}.c-header__search-layout>:first-child{flex:999 1 auto}.c-header__search-layout>*{flex:1 1 auto}.c-header__search-layout--max-width{max-width:720px}.c-header__search-button{align-items:center;background-color:transparent;background-image:none;border:1px solid #fff;border-radius:2px;color:#fff;cursor:pointer;display:flex;font-family:sans-serif;font-size:1rem;justify-content:center;line-height:1.15;margin:0;padding:8px 16px;position:relative;text-decoration:none;transition:all .25s ease 0s,color .25s ease 0s,border-color .25s ease 0s;width:100%}.u-button svg,.u-button--primary svg{fill:currentcolor}.c-header__input,.c-header__select{border:1px solid;border-radius:3px;box-sizing:border-box;font-size:1rem;padding:8px 16px;width:100%}.c-header__select{-webkit-appearance:none;background-image:url("data:image/svg+xml,%3Csvg height='16' viewBox='0 0 16 16' width='16' xmlns='http://www.w3.org/2000/svg'%3E%3Cpath d='m5.58578644 3-3.29289322-3.29289322c-.39052429-.39052429-.39052429-1.02368927 0-1.41421356s1.02368927-.39052429 1.41421356 0l4 4c.39052429.39052429.39052429 1.02368927 0 1.41421356l-4 4c-.39052429.39052429-1.02368927.39052429-1.41421356 0s-.39052429-1.02368927 0-1.41421356z' fill='%23333' fill-rule='evenodd' transform='matrix(0 1 -1 0 11 3)'/%3E%3C/svg%3E");background-position:right .7em top 50%;background-repeat:no-repeat;background-size:1em;box-shadow:0 1px 0 1px rgba(0,0,0,.04);display:block;margin:0;max-width:100%;min-width:150px}@media only screen and (min-width:540px){.c-header__menu--journal .c-header__item--dropdown-menu:last-child .c-header__dropdown.has-tethered{left:auto;right:0}}@media only screen and (min-width:768px){.c-header__menu--journal .c-header__item--dropdown-menu:last-child .c-header__dropdown.has-tethered{left:0;right:auto}}.c-header__dropdown.has-tethered{border-bottom:0;border-radius:0 0 2px 2px;left:0;position:absolute;top:100%;transform:translateY(5px);width:100%;z-index:1}@media only screen and (min-width:540px){.c-header__dropdown.has-tethered{transform:translateY(8px);width:auto}}@media only screen and (min-width:768px){.c-header__dropdown.has-tethered{min-width:225px}}.c-header__dropdown--full-width.has-tethered{padding:32px 0 24px;transform:none;width:100%}.has-tethered .c-header__heading--js-hide{display:none;visibility:hidden}.has-tethered .c-header__list--js-stack{flex-direction:column}.has-tethered .c-header__item--keyline,.has-tethered .c-header__list~.c-header__list .c-header__item:first-child{border-top:1px solid #d5d5d5;margin-top:8px;padding-top:8px}.c-header__item--snid-account-widget{display:flex}.c-header__container{padding:0 4px}.c-header__list{padding:0 12px}.c-header__menu .c-header__link{font-size:14px}.c-header__item--snid-account-widget .c-header__link{padding:8px}.c-header__menu--journal{margin-left:0}@media only screen and (min-width:540px){.c-header__container{padding:0 16px}.c-header__menu--journal{margin-left:-8px}.c-header__menu .c-header__link{font-size:16px}.c-header__link--search{gap:13px 13px}}.u-button{align-items:center;background-color:transparent;background-image:none;border:1px solid #069;border-radius:2px;color:#069;cursor:pointer;display:inline-flex;font-family:sans-serif;font-size:1rem;justify-content:center;line-height:1.3;margin:0;padding:8px;position:relative;text-decoration:none;transition:all .25s ease 0s,color .25s ease 0s,border-color .25s ease 0s;width:auto}.u-button--primary{background-color:#069;background-image:none;border:1px solid #069;color:#fff}.u-button--full-width{display:flex;width:100%}.u-display-none{display:none}.js .u-js-hide,.u-hide{display:none;visibility:hidden}.u-hide:first-child+*{margin-block-start:0}.u-visually-hidden{clip:rect(0,0,0,0);border:0;height:1px;margin:-100%;overflow:hidden;padding:0;position:absolute!important;width:1px}@media print{.u-hide-print{display:none}}@media only screen and (min-width:1024px){.u-hide-at-lg{display:none;visibility:hidden}.u-hide-at-lg:first-child+*{margin-block-start:0}}.u-clearfix:after,.u-clearfix:before{content:"";display:table}.u-clearfix:after{clear:both}.u-color-open-access{color:#b74616}.u-float-left{float:left}.u-icon{fill:currentcolor;display:inline-block;height:1em;transform:translate(0);vertical-align:text-top;width:1em}.u-full-height{height:100%}.u-list-reset{list-style:none;margin:0;padding:0}.u-sans-serif{font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif}.u-container{margin:0 auto;max-width:1280px;padding:0 16px}.u-justify-content-space-between{justify-content:space-between}.u-mt-32{margin-top:32px}.u-mb-8{margin-bottom:8px}.u-mb-16{margin-bottom:16px}.u-mb-24{margin-bottom:24px}.u-mb-32{margin-bottom:32px}.c-nature-box svg+.c-article__button-text,.u-ml-8{margin-left:8px}.u-pa-16{padding:16px}html *,html :after,html :before{box-sizing:inherit}.c-article-section__title,.c-article-title{font-weight:700}.c-card__title{line-height:1.4em}.c-article__button{background-color:#069;border:1px solid #069;border-radius:2px;color:#fff;display:flex;font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif;font-size:.875rem;line-height:1.4;margin-bottom:16px;padding:13px;transition:background-color .2s ease-out 0s,color .2s ease-out 0s}.c-article__button,.c-article__button:hover{text-decoration:none}.c-article__button--inverted,.c-article__button:hover{background-color:#fff;color:#069}.c-article__button--inverted:hover{background-color:#069;color:#fff}.c-header__link{text-decoration:inherit}.grade-c-hide{display:block}.u-lazy-ad-wrapper{background-color:#ccc;display:none;min-height:137px}@media only screen and (min-width:768px){.u-lazy-ad-wrapper{display:block}}.c-nature-box{background-color:#fff;border:1px solid #d5d5d5;border-radius:2px;box-shadow:0 0 5px 0 rgba(51,51,51,.1);line-height:1.3;margin-bottom:24px;padding:16px 16px 3px}.c-nature-box__text{font-size:1rem;margin-bottom:16px}.c-nature-box .c-pdf-download{margin-bottom:16px!important}.c-nature-box--version{background-color:#eee}.c-nature-box__wrapper{transform:translateZ(0)}.c-nature-box__wrapper--placeholder{min-height:165px}.c-pdf-download__link{padding:13px 24px} } </style> <link data-test="critical-css-handler" data-inline-css-source="critical-css" rel="stylesheet" href="/static/css/enhanced-article-nature-branded-68c4876c28.css" media="print" onload="this.media='only print, only all and (prefers-color-scheme: no-preference), only all and (prefers-color-scheme: light), only all and (prefers-color-scheme: dark)';this.onload=null"> <noscript> <link rel="stylesheet" type="text/css" href="/static/css/enhanced-article-nature-branded-68c4876c28.css" media="only print, only all and (prefers-color-scheme: no-preference), only all and (prefers-color-scheme: light), only all and (prefers-color-scheme: dark)"> </noscript> <link rel="stylesheet" type="text/css" href="/static/css/article-print-122346e276.css" media="print"> <link rel="apple-touch-icon" sizes="180x180" href=/static/images/favicons/nature/apple-touch-icon-f39cb19454.png> <link rel="icon" type="image/png" sizes="48x48" href=/static/images/favicons/nature/favicon-48x48-b52890008c.png> <link rel="icon" type="image/png" sizes="32x32" href=/static/images/favicons/nature/favicon-32x32-3fe59ece92.png> <link rel="icon" type="image/png" sizes="16x16" href=/static/images/favicons/nature/favicon-16x16-951651ab72.png> <link rel="manifest" href=/static/manifest.json crossorigin="use-credentials"> <link rel="mask-icon" href=/static/images/favicons/nature/safari-pinned-tab-69bff48fe6.svg color="#000000"> <link rel="shortcut icon" href=/static/images/favicons/nature/favicon.ico> <meta name="msapplication-TileColor" content="#000000"> <meta name="msapplication-config" content=/static/browserconfig.xml> <meta name="theme-color" content="#000000"> <meta name="application-name" content="Nature"> <script> (function () { if ( typeof window.CustomEvent === "function" ) return false; function CustomEvent ( event, params ) { params = params || { bubbles: false, cancelable: false, detail: null }; var evt = document.createEvent( 'CustomEvent' ); evt.initCustomEvent( event, params.bubbles, params.cancelable, params.detail ); return evt; } CustomEvent.prototype = window.Event.prototype; window.CustomEvent = CustomEvent; })(); </script>  <script data-test="gtm-head"> window.initGTM = function() { if (window.config.mustardcut) { (function (w, d, s, l, i) { w[l] = w[l] || []; w[l].push({'gtm.start': new Date().getTime(), event: 'gtm.js'}); var f = d.getElementsByTagName(s)[0], j = d.createElement(s), dl = l != 'dataLayer' ? '&l=' + l : ''; j.async = true; j.src = 'https://www.googletagmanager.com/gtm.js?id=' + i + dl; f.parentNode.insertBefore(j, f); })(window, document, 'script', 'dataLayer', 'GTM-MRVXSHQ'); } } </script>  <script> (function(w,d,t) { function cc() { var h = w.location.hostname; if (h.indexOf('preview-www.nature.com') > -1) return; var e = d.createElement(t), s = d.getElementsByTagName(t)[0]; if (h.indexOf('nature.com') > -1) { if (h.indexOf('test-www.nature.com') > -1) { e.src = 'https://cmp.nature.com/production_live/en/consent-bundle-8-68.js'; e.setAttribute('onload', "initGTM(window,document,'script','dataLayer','GTM-MRVXSHQ')"); } else { e.src = 'https://cmp.nature.com/production_live/en/consent-bundle-8-68.js'; e.setAttribute('onload', "initGTM(window,document,'script','dataLayer','GTM-MRVXSHQ')"); } } else { e.src = '/static/js/cookie-consent-es5-bundle-cb57c2c98a.js'; e.setAttribute('data-consent', h); } s.insertAdjacentElement('afterend', e); } cc(); })(window,document,'script'); </script> <script id="js-position0"> (function(w, d) { w.idpVerifyPrefix = 'https://verify.nature.com'; w.ra21Host = 'https://wayf.springernature.com'; var moduleSupport = (function() { return 'noModule' in d.createElement('script'); })(); if (w.config.mustardcut === true) { w.loader = { index: 0, registered: [], scripts: [ {src: '/static/js/global-article-es6-bundle-c8a573ca90.js', test: 'global-article-js', module: true}, {src: '/static/js/global-article-es5-bundle-d17603b9e9.js', test: 'global-article-js', nomodule: true}, {src: '/static/js/shared-es6-bundle-606cb67187.js', test: 'shared-js', module: true}, {src: '/static/js/shared-es5-bundle-e919764a53.js', test: 'shared-js', nomodule: true}, {src: '/static/js/header-150-es6-bundle-5bb959eaa1.js', test: 'header-150-js', module: true}, {src: '/static/js/header-150-es5-bundle-994fde5b1d.js', test: 'header-150-js', nomodule: true} ].filter(function (s) { if (s.src === null) return false; if (moduleSupport && s.nomodule) return false; return !(!moduleSupport && s.module); }), register: function (value) { this.registered.push(value); }, ready: function () { if (this.registered.length === this.scripts.length) { this.registered.forEach(function (fn) { if (typeof fn === 'function') { setTimeout(fn, 0); } }); this.ready = function () {}; } }, insert: function (s) { var t = d.getElementById('js-position' + this.index); if (t && t.insertAdjacentElement) { t.insertAdjacentElement('afterend', s); } else { d.head.appendChild(s); } ++this.index; }, createScript: function (script, beforeLoad) { var s = d.createElement('script'); s.id = 'js-position' + (this.index + 1); s.setAttribute('data-test', script.test); if (beforeLoad) { s.defer = 'defer'; s.onload = function () { if (script.noinit) { loader.register(true); } if (d.readyState === 'interactive' || d.readyState === 'complete') { loader.ready(); } }; } else { s.async = 'async'; } s.src = script.src; return s; }, init: function () { this.scripts.forEach(function (s) { loader.insert(loader.createScript(s, true)); }); d.addEventListener('DOMContentLoaded', function () { loader.ready(); var conditionalScripts; conditionalScripts = [ {match: 'div[data-pan-container]', src: '/static/js/pan-zoom-es6-bundle-464a2af269.js', test: 'pan-zoom-js', module: true }, {match: 'div[data-pan-container]', src: '/static/js/pan-zoom-es5-bundle-98fb9b653b.js', test: 'pan-zoom-js', nomodule: true }, {match: 'math,span.mathjax-tex', src: '/static/js/math-es6-bundle-23597ae350.js', test: 'math-js', module: true}, {match: 'math,span.mathjax-tex', src: '/static/js/math-es5-bundle-6532c6f78b.js', test: 'math-js', nomodule: true} ]; if (conditionalScripts) { conditionalScripts.filter(function (script) { return !!document.querySelector(script.match) && !((moduleSupport && script.nomodule) || (!moduleSupport && script.module)); }).forEach(function (script) { loader.insert(loader.createScript(script)); }); } }, false); } }; loader.init(); } })(window, document); </script> <meta name="robots" content="noarchive"> <meta name="access" content="Yes"> <link rel="search" href="https://www.nature.com/search"> <link rel="search" href="https://www.nature.com/opensearch/opensearch.xml" type="application/opensearchdescription+xml" title="nature.com"> <link rel="search" href="https://www.nature.com/opensearch/request" type="application/sru+xml" title="nature.com"> <script type="application/ld+json">{"mainEntity":{"headline":"Chemical logic of MraY inhibition by antibacterial nucleoside natural products","description":"Novel antibacterial agents are needed to address the emergence of global antibiotic resistance. MraY is a promising candidate for antibiotic development because it is the target of five classes of naturally occurring nucleoside inhibitors with potent antibacterial activity. Although these natural products share a common uridine moiety, their core structures vary substantially and they exhibit different activity profiles. An incomplete understanding of the structural and mechanistic basis of MraY inhibition has hindered the translation of these compounds to the clinic. Here we present crystal structures of MraY in complex with representative members of the liposidomycin/caprazamycin, capuramycin, and mureidomycin classes of nucleoside inhibitors. Our structures reveal cryptic druggable hot spots in the shallow inhibitor binding site of MraY that were not previously appreciated. Structural analyses of nucleoside inhibitor binding provide insights into the chemical logic of MraY inhibition, which can guide novel approaches to MraY-targeted antibiotic design. Phospho-MurNAc-pentapeptide translocase (MraY) is a bacterial integral membrane enzyme that is essential for peptidoglycan biosynthesis. Here the authors present the crystal structures of MraY from Aquifex aeolicus bound to caprazamycin, capuramycin and mureidomycin and discuss the implications for antibiotic development.","datePublished":"2019-07-02T00:00:00Z","dateModified":"2019-07-02T00:00:00Z","pageStart":"1","pageEnd":"12","license":"http://creativecommons.org/licenses/by/4.0/","sameAs":"https://doi.org/10.1038/s41467-019-10957-9","keywords":["Antibiotics","Transferases","X-ray crystallography","Science","Humanities and Social Sciences","multidisciplinary"],"image":["https://media.springernature.com/lw1200/springer-static/image/art%3A10.1038%2Fs41467-019-10957-9/MediaObjects/41467_2019_10957_Fig1_HTML.png","https://media.springernature.com/lw1200/springer-static/image/art%3A10.1038%2Fs41467-019-10957-9/MediaObjects/41467_2019_10957_Fig2_HTML.png","https://media.springernature.com/lw1200/springer-static/image/art%3A10.1038%2Fs41467-019-10957-9/MediaObjects/41467_2019_10957_Fig3_HTML.png","https://media.springernature.com/lw1200/springer-static/image/art%3A10.1038%2Fs41467-019-10957-9/MediaObjects/41467_2019_10957_Fig4_HTML.png","https://media.springernature.com/lw1200/springer-static/image/art%3A10.1038%2Fs41467-019-10957-9/MediaObjects/41467_2019_10957_Fig5_HTML.png","https://media.springernature.com/lw1200/springer-static/image/art%3A10.1038%2Fs41467-019-10957-9/MediaObjects/41467_2019_10957_Fig6_HTML.png"],"isPartOf":{"name":"Nature Communications","issn":["2041-1723"],"volumeNumber":"10","@type":["Periodical","PublicationVolume"]},"publisher":{"name":"Nature Publishing Group UK","logo":{"url":"https://www.springernature.com/app-sn/public/images/logo-springernature.png","@type":"ImageObject"},"@type":"Organization"},"author":[{"name":"Ellene H. Mashalidis","affiliation":[{"name":"Duke University Medical Center","address":{"name":"Department of Biochemistry, Duke University Medical Center, Durham, USA","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Benjamin Kaeser","affiliation":[{"name":"Duke University Medical Center","address":{"name":"Department of Biochemistry, Duke University Medical Center, Durham, USA","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Yuma Terasawa","affiliation":[{"name":"Hokkaido University","address":{"name":"Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Akira Katsuyama","url":"http://orcid.org/0000-0002-4062-5561","affiliation":[{"name":"Hokkaido University","address":{"name":"Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Do-Yeon Kwon","affiliation":[{"name":"Duke University","address":{"name":"Department of Chemistry, Duke University, Durham, USA","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Kiyoun Lee","affiliation":[{"name":"The Catholic University of Korea","address":{"name":"Department of Chemistry, The Catholic University of Korea, Bucheon, Korea","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Jiyong Hong","url":"http://orcid.org/0000-0002-5253-0949","affiliation":[{"name":"Duke University","address":{"name":"Department of Chemistry, Duke University, Durham, USA","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Satoshi Ichikawa","affiliation":[{"name":"Hokkaido University","address":{"name":"Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Seok-Yong Lee","url":"http://orcid.org/0000-0002-0662-9921","affiliation":[{"name":"Duke University Medical Center","address":{"name":"Department of Biochemistry, Duke University Medical Center, Durham, USA","@type":"PostalAddress"},"@type":"Organization"}],"email":"seok-yong.lee@duke.edu","@type":"Person"}],"isAccessibleForFree":true,"@type":"ScholarlyArticle"},"@context":"https://schema.org","@type":"WebPage"}</script> <link rel="canonical" href="https://www.nature.com/articles/s41467-019-10957-9"> <meta name="journal_id" content="41467"/> <meta name="dc.title" content="Chemical logic of MraY inhibition by antibacterial nucleoside natural products"/> <meta name="dc.source" content="Nature Communications 2019 10:1"/> <meta name="dc.format" content="text/html"/> <meta name="dc.publisher" content="Nature Publishing Group"/> <meta name="dc.date" content="2019-07-02"/> <meta name="dc.type" content="OriginalPaper"/> <meta name="dc.language" content="En"/> <meta name="dc.copyright" content="2019 The Author(s)"/> <meta name="dc.rights" content="2019 The Author(s)"/> <meta name="dc.rightsAgent" content="journalpermissions@springernature.com"/> <meta name="dc.description" content="Novel antibacterial agents are needed to address the emergence of global antibiotic resistance. MraY is a promising candidate for antibiotic development because it is the target of five classes of naturally occurring nucleoside inhibitors with potent antibacterial activity. Although these natural products share a common uridine moiety, their core structures vary substantially and they exhibit different activity profiles. An incomplete understanding of the structural and mechanistic basis of MraY inhibition has hindered the translation of these compounds to the clinic. Here we present crystal structures of MraY in complex with representative members of the liposidomycin/caprazamycin, capuramycin, and mureidomycin classes of nucleoside inhibitors. Our structures reveal cryptic druggable hot spots in the shallow inhibitor binding site of MraY that were not previously appreciated. Structural analyses of nucleoside inhibitor binding provide insights into the chemical logic of MraY inhibition, which can guide novel approaches to MraY-targeted antibiotic design. Phospho-MurNAc-pentapeptide translocase (MraY) is a bacterial integral membrane enzyme that is essential for peptidoglycan biosynthesis. Here the authors present the crystal structures of MraY from Aquifex aeolicus bound to caprazamycin, capuramycin and mureidomycin and discuss the implications for antibiotic development."/> <meta name="prism.issn" content="2041-1723"/> <meta name="prism.publicationName" content="Nature Communications"/> <meta name="prism.publicationDate" content="2019-07-02"/> <meta name="prism.volume" content="10"/> <meta name="prism.number" content="1"/> <meta name="prism.section" content="OriginalPaper"/> <meta name="prism.startingPage" content="1"/> <meta name="prism.endingPage" content="12"/> <meta name="prism.copyright" content="2019 The Author(s)"/> <meta name="prism.rightsAgent" content="journalpermissions@springernature.com"/> <meta name="prism.url" content="https://www.nature.com/articles/s41467-019-10957-9"/> <meta name="prism.doi" content="doi:10.1038/s41467-019-10957-9"/> <meta name="citation_pdf_url" content="https://www.nature.com/articles/s41467-019-10957-9.pdf"/> <meta name="citation_fulltext_html_url" content="https://www.nature.com/articles/s41467-019-10957-9"/> <meta name="citation_journal_title" content="Nature Communications"/> <meta name="citation_journal_abbrev" content="Nat Commun"/> <meta name="citation_publisher" content="Nature Publishing Group"/> <meta name="citation_issn" content="2041-1723"/> <meta name="citation_title" content="Chemical logic of MraY inhibition by antibacterial nucleoside natural products"/> <meta name="citation_volume" content="10"/> <meta name="citation_issue" content="1"/> <meta name="citation_online_date" content="2019/07/02"/> <meta name="citation_firstpage" content="1"/> <meta name="citation_lastpage" content="12"/> <meta name="citation_article_type" content="Article"/> <meta name="citation_fulltext_world_readable" content=""/> <meta name="citation_language" content="en"/> <meta name="dc.identifier" content="doi:10.1038/s41467-019-10957-9"/> <meta name="DOI" content="10.1038/s41467-019-10957-9"/> <meta name="size" content="220182"/> <meta name="citation_doi" content="10.1038/s41467-019-10957-9"/> <meta name="citation_springer_api_url" content="http://api.springer.com/xmldata/jats?q=doi:10.1038/s41467-019-10957-9&api_key="/> <meta name="description" content="Novel antibacterial agents are needed to address the emergence of global antibiotic resistance. MraY is a promising candidate for antibiotic development because it is the target of five classes of naturally occurring nucleoside inhibitors with potent antibacterial activity. Although these natural products share a common uridine moiety, their core structures vary substantially and they exhibit different activity profiles. An incomplete understanding of the structural and mechanistic basis of MraY inhibition has hindered the translation of these compounds to the clinic. Here we present crystal structures of MraY in complex with representative members of the liposidomycin/caprazamycin, capuramycin, and mureidomycin classes of nucleoside inhibitors. Our structures reveal cryptic druggable hot spots in the shallow inhibitor binding site of MraY that were not previously appreciated. Structural analyses of nucleoside inhibitor binding provide insights into the chemical logic of MraY inhibition, which can guide novel approaches to MraY-targeted antibiotic design. Phospho-MurNAc-pentapeptide translocase (MraY) is a bacterial integral membrane enzyme that is essential for peptidoglycan biosynthesis. Here the authors present the crystal structures of MraY from Aquifex aeolicus bound to caprazamycin, capuramycin and mureidomycin and discuss the implications for antibiotic development."/> <meta name="dc.creator" content="Mashalidis, Ellene H."/> <meta name="dc.creator" content="Kaeser, Benjamin"/> <meta name="dc.creator" content="Terasawa, Yuma"/> <meta name="dc.creator" content="Katsuyama, Akira"/> <meta name="dc.creator" content="Kwon, Do-Yeon"/> <meta name="dc.creator" content="Lee, Kiyoun"/> <meta name="dc.creator" content="Hong, Jiyong"/> <meta name="dc.creator" content="Ichikawa, Satoshi"/> <meta name="dc.creator" content="Lee, Seok-Yong"/> <meta name="dc.subject" content="Antibiotics"/> <meta name="dc.subject" content="Transferases"/> <meta name="dc.subject" content="X-ray crystallography"/> <meta name="citation_reference" content="Tackling Drug-Resistant infections Globally: Final Report and Recommendations. Rev. Antimicrob. Resist. (2016). https://amrreview.org/ ."/> <meta name="citation_reference" content="citation_journal_title=Nat. Rev. Microbiol; citation_title=Molecular mechanisms of antibiotic resistance; citation_author=JM Blair, MA Webber, AJ Baylay, DO Ogbolu, LJ Piddock; citation_volume=13; citation_publication_date=2015; citation_pages=42-51; citation_doi=10.1038/nrmicro3380; citation_id=CR2"/> <meta name="citation_reference" content="citation_journal_title=Drug Disco. Today; citation_title=Structural basis for selective inhibition of antibacterial target MraY, a membrane-bound enzyme involved in peptidoglycan synthesis; citation_author=J Hering, E Dunevall, M Ek, G Branden; citation_volume=23; citation_publication_date=2018; citation_pages=1426-1435; citation_doi=10.1016/j.drudis.2018.05.020; citation_id=CR3"/> <meta name="citation_reference" content="citation_journal_title=Angew. Chem. Int Ed. Engl.; citation_title=Natural Products at Work: structural Insights into Inhibition of the Bacterial Membrane Protein MraY; citation_author=S Koppermann, C Ducho; citation_volume=55; citation_publication_date=2016; citation_pages=11722-11724; citation_doi=10.1002/anie.201606396; citation_id=CR4"/> <meta name="citation_reference" content="citation_journal_title=ChemMedChem; citation_title=Insights into the target interaction of naturally occurring muraymycin nucleoside antibiotics; citation_author=S Koppermann; citation_volume=13; citation_publication_date=2018; citation_pages=779-784; citation_doi=10.1002/cmdc.201700793; citation_id=CR5"/> <meta name="citation_reference" content="citation_journal_title=Nat. Prod. Rep.; citation_title=Antimicrobial nucleoside antibiotics targeting cell wall assembly: recent advances in structure-function studies and nucleoside biosynthesis; citation_author=M Winn, RJ Goss, K Kimura, TD Bugg; citation_volume=27; citation_publication_date=2010; citation_pages=279-304; citation_doi=10.1039/B816215H; citation_id=CR6"/> <meta name="citation_reference" content="citation_journal_title=Curr. Med Chem.; citation_title=Antibacterial nucleoside natural products inhibiting phospho-MurNAc-pentapeptide translocase; chemistry and structure-activity relationship; citation_author=S Ichikawa, M Yamaguchi, A Matsuda; citation_volume=22; citation_publication_date=2015; citation_pages=3951-3979; citation_doi=10.2174/0929867322666150818103502; citation_id=CR7"/> <meta name="citation_reference" content="citation_journal_title=Antimicrob. Agents Chemother.; citation_title=Modes of action of tunicamycin, liposidomycin B, and mureidomycin A: inhibition of phospho-N-acetylmuramyl-pentapeptide translocase from Escherichia coli; citation_author=PE Brandish; citation_volume=40; citation_publication_date=1996; citation_pages=1640-1644; citation_doi=10.1128/AAC.40.7.1640; citation_id=CR8"/> <meta name="citation_reference" content="citation_journal_title=Biol. Act. A-500359 A, C., D. G. J. Antibiot. (Tokyo); citation_title=Studies on novel bacterial translocase I inhibitors, A-500359s. II; citation_author=Y Muramatsu, MM Ishii, M Inukai; citation_volume=56; citation_publication_date=2003; citation_pages=253-258; citation_id=CR9"/> <meta name="citation_reference" content="citation_journal_title=J. Biol. Chem.; citation_title=Slow binding inhibition of phospho-N-acetylmuramyl-pentapeptide-translocase (Escherichia coli) by mureidomycin A; citation_author=PE Brandish; citation_volume=271; citation_publication_date=1996; citation_pages=7609-7614; citation_doi=10.1074/jbc.271.13.7609; citation_id=CR10"/> <meta name="citation_reference" content="citation_journal_title=J. Biol. Chem.; citation_title=Relationship of the structure and biological activity of the natural homologues of tunicamycin; citation_author=D Duksin, WC Mahoney; citation_volume=257; citation_publication_date=1982; citation_pages=3105-3109; citation_id=CR11"/> <meta name="citation_reference" content="citation_journal_title=Antimicrob. Agents Chemother.; citation_title=Selective inhibition of the bacterial translocase reaction in peptidoglycan synthesis by mureidomycins; citation_author=M Inukai, F Isono, A Takatsuki; citation_volume=37; citation_publication_date=1993; citation_pages=980-983; citation_doi=10.1128/AAC.37.5.980; citation_id=CR12"/> <meta name="citation_reference" content="citation_journal_title=Nat. Chem. Biol.; citation_title=MraY-antibiotic complex reveals details of tunicamycin mode of action; citation_author=JK Hakulinen; citation_volume=13; citation_publication_date=2017; citation_pages=265-267; citation_doi=10.1038/nchembio.2270; citation_id=CR13"/> <meta name="citation_reference" content="citation_journal_title=Nat. Struct. Mol. Biol.; citation_title=GlcNAc-1-P-transferase-tunicamycin complex structure reveals basis for inhibition of N-glycosylation; citation_author=J Yoo; citation_volume=25; citation_publication_date=2018; citation_pages=217-224; citation_doi=10.1038/s41594-018-0031-y; citation_id=CR14"/> <meta name="citation_reference" content="citation_journal_title=Cell; citation_title=Structures of DPAGT1 explain glycosylation disease mechanisms and advance TB antibiotic design; citation_author=YY Dong; citation_volume=175; citation_publication_date=2018; citation_pages=1045-1058; citation_doi=10.1016/j.cell.2018.10.037; citation_id=CR15"/> <meta name="citation_reference" content="citation_journal_title=Drug Disco. Today; citation_title=Druggable pockets and binding site centric chemical space: a paradigm shift in drug discovery; citation_author=S Perot, O Sperandio, MA Miteva, AC Camproux, BO Villoutreix; citation_volume=15; citation_publication_date=2010; citation_pages=656-667; citation_doi=10.1016/j.drudis.2010.05.015; citation_id=CR16"/> <meta name="citation_reference" content="citation_journal_title=Science; citation_title=Crystal structure of MraY, an essential membrane enzyme for bacterial cell wall synthesis; citation_author=BC Chung; citation_volume=341; citation_publication_date=2013; citation_pages=1012-1016; citation_doi=10.1126/science.1236501; citation_id=CR17"/> <meta name="citation_reference" content="citation_journal_title=Nature; citation_title=Structural insights into inhibition of lipid I production in bacterial cell wall synthesis; citation_author=BC Chung; citation_volume=533; citation_publication_date=2016; citation_pages=557-560; citation_doi=10.1038/nature17636; citation_id=CR18"/> <meta name="citation_reference" content="citation_journal_title=J. Org. Chem.; citation_title=Synthesis of caprazamycin analogues and their structure–activity relationship for antibacterial activity; citation_author=S Hirano, S Ichikawa, A Matsuda; citation_volume=73; citation_publication_date=2008; citation_pages=569-577; citation_doi=10.1021/jo702264e; citation_id=CR19"/> <meta name="citation_reference" content="citation_journal_title=Biol. Prop. J. Antibiot. (Tokyo); citation_title=novel peptidylnucleoside antibiotics with spheroplast forming activity. III; citation_author=F Isono, T Katayama, M Inukai, T Haneishi, A-D Mureidomycins; citation_volume=42; citation_publication_date=1989; citation_pages=674-679; citation_doi=10.7164/antibiotics.42.674; citation_id=CR20"/> <meta name="citation_reference" content="citation_journal_title=Antimicrob. Agents Chemother.; citation_title=Susceptibility of Pseudomonas species to the novel antibiotics mureidomycins; citation_author=F Isono, K Kodama, M Inukai; citation_volume=36; citation_publication_date=1992; citation_pages=1024-1027; citation_doi=10.1128/AAC.36.5.1024; citation_id=CR21"/> <meta name="citation_reference" content="citation_journal_title=Bioorg. Med Chem. Lett.; citation_title=Synthesis and antimycobacterial activity of capuramycin analogues. Part 1: substitution of the azepan-2-one moiety of capuramycin; citation_author=H Hotoda; citation_volume=13; citation_publication_date=2003; citation_pages=2829-2832; citation_doi=10.1016/S0960-894X(03)00596-1; citation_id=CR22"/> <meta name="citation_reference" content="citation_journal_title=Bioorg. Med Chem. Lett.; citation_title=Synthesis and antimycobacterial activity of capuramycin analogues. Part 2: acylated derivatives of capuramycin-related compounds; citation_author=H Hotoda; citation_volume=13; citation_publication_date=2003; citation_pages=2833-2836; citation_doi=10.1016/S0960-894X(03)00597-3; citation_id=CR23"/> <meta name="citation_reference" content="citation_journal_title=Antimicrob. Agents Chemother.; citation_title=In vitro antimycobacterial activities of capuramycin analogues; citation_author=VM Reddy, L Einck, CA Nacy; citation_volume=52; citation_publication_date=2008; citation_pages=719-721; citation_doi=10.1128/AAC.01469-07; citation_id=CR24"/> <meta name="citation_reference" content="citation_journal_title=Agric. Biol. Chem.; citation_title=Liposidomycin C inhibits phospho-N-acetylmuramyl-pentapeptide transferase in peptidoglycan synthesis of Escherichia coli Y-10; citation_author=K-i Kimura; citation_volume=53; citation_publication_date=1989; citation_pages=1811-1815; citation_id=CR25"/> <meta name="citation_reference" content="citation_journal_title=ACS Infect. Dis.; citation_title=Carbacaprazamycins: chemically stable analogues of the caprazamycin nucleoside antibiotics; citation_author=S Ichikawa, M Yamaguchi, LS Hsuan, Y Kato, A Matsuda; citation_volume=1; citation_publication_date=2015; citation_pages=151-156; citation_doi=10.1021/id5000376; citation_id=CR26"/> <meta name="citation_reference" content="citation_journal_title=Antimicrob. Agents Chemother.; citation_title=Mureidomycin A, a new inhibitor of bacterial peptidoglycan synthesis; citation_author=F Isono, M Inukai; citation_volume=35; citation_publication_date=1991; citation_pages=234-236; citation_doi=10.1128/AAC.35.2.234; citation_id=CR27"/> <meta name="citation_reference" content="citation_journal_title=J. Med. Chem.; citation_title=Mechanistic analysis of muraymycin analogues: a guide to the design of MraY inhibitors; citation_author=T Tanino; citation_volume=54; citation_publication_date=2011; citation_pages=8421-8439; citation_doi=10.1021/jm200906r; citation_id=CR28"/> <meta name="citation_reference" content="Yamamoto, K., Katsuyama, A. & Ichikawa, S. Structural requirement of tunicamycin V for MraY inhibition. Bioorg. Med. Chem. Lett. 27, 1714–1719 (2019)."/> <meta name="citation_reference" content="citation_journal_title=Bioorg. Med Chem.; citation_title=Design and synthesis of diketopiperazine and acyclic analogs related to the caprazamycins and liposidomycins as potential antibacterial agents; citation_author=S Hirano, S Ichikawa, A Matsuda; citation_volume=16; citation_publication_date=2008; citation_pages=428-436; citation_doi=10.1016/j.bmc.2007.09.022; citation_id=CR30"/> <meta name="citation_reference" content="citation_journal_title=Bioorg. Med Chem.; citation_title=Structure-activity relationship of truncated analogs of caprazamycins as potential anti-tuberculosis agents; citation_author=S Hirano, S Ichikawa, A Matsuda; citation_volume=16; citation_publication_date=2008; citation_pages=5123-5133; citation_doi=10.1016/j.bmc.2008.03.020; citation_id=CR31"/> <meta name="citation_reference" content="citation_journal_title=J. Antibiot. (Tokyo); citation_title=Studies on novel bacterial translocase I inhibitors, A-500359s. III. Deaminocaprolactam derivatives of capuramycin: A-500359 E, F, H; M-1 and M-2; citation_author=Y Muramatsu; citation_volume=56; citation_publication_date=2003; citation_pages=259-267; citation_doi=10.7164/antibiotics.56.259; citation_id=CR32"/> <meta name="citation_reference" content="citation_journal_title=J. Org. Chem.; citation_title=Total synthesis and biological evaluation of pacidamycin D and its 3′-hydroxy analogue; citation_author=K Okamoto; citation_volume=77; citation_publication_date=2012; citation_pages=1367-1377; citation_doi=10.1021/jo202159q; citation_id=CR33"/> <meta name="citation_reference" content="citation_journal_title=Bioorg. Med Chem. Lett.; citation_title=Synthesis of analogues of the O-beta-D-ribofuranosyl nucleoside moiety of liposidomycins. Part 1: contribution of the amino group and the uracil moiety upon the inhibition of MraY; citation_author=C Dini; citation_volume=11; citation_publication_date=2001; citation_pages=529-531; citation_doi=10.1016/S0960-894X(00)00715-0; citation_id=CR34"/> <meta name="citation_reference" content="citation_journal_title=J. Antibiot. (Tokyo); citation_title=Mureidomycins E and F, minor components of mureidomycins; citation_author=F Isono; citation_volume=46; citation_publication_date=1993; citation_pages=1203-1207; citation_doi=10.7164/antibiotics.46.1203; citation_id=CR35"/> <meta name="citation_reference" content="citation_journal_title=J. Antibiot. (Tokyo); citation_title=Napsamycins, new Pseudomonas active antibiotics of the mureidomycin family from Streptomyces sp. HIL Y-82,11372; citation_author=S Chatterjee; citation_volume=47; citation_publication_date=1994; citation_pages=595-598; citation_doi=10.7164/antibiotics.47.595; citation_id=CR36"/> <meta name="citation_reference" content="citation_journal_title=J. Am. Chem. Soc.; citation_title=Structures of the muraymycins, novel peptidoglycan biosynthesis inhibitors; citation_author=LA McDonald; citation_volume=124; citation_publication_date=2002; citation_pages=10260-10261; citation_doi=10.1021/ja017748h; citation_id=CR37"/> <meta name="citation_reference" content="citation_journal_title=Chemistry; citation_title=Lead structures for new antibacterials: stereocontrolled synthesis of a bioactive muraymycin analogue; citation_author=AP Spork; citation_volume=20; citation_publication_date=2014; citation_pages=15292-15297; citation_doi=10.1002/chem.201404775; citation_id=CR38"/> <meta name="citation_reference" content="Spork, A. P., Koppermann, S., Schier Nee Wohnig, S., Linder, R. & Ducho, C. Analogues of muraymycin nucleoside antibiotics with epimeric uridine-derived core structures. Molecules 23, 2868–2888 (2018)."/> <meta name="citation_reference" content="citation_journal_title=Biochemistry; citation_title=Active site mapping of MraY, a member of the polyprenyl-phosphate N-acetylhexosamine 1-phosphate transferase superfamily, catalyzing the first membrane step of peptidoglycan biosynthesis; citation_author=B Al-Dabbagh; citation_volume=47; citation_publication_date=2008; citation_pages=8919-8928; citation_doi=10.1021/bi8006274; citation_id=CR40"/> <meta name="citation_reference" content="citation_journal_title=Bioorg. Med. Chem.; citation_title=Synthesis and activity of 5′-Uridinyl dipeptide analogues mimicking the amino terminal peptide chain of nucleoside antibiotic mureidomycin A; citation_author=NI Howard, TDH Bugg; citation_volume=11; citation_publication_date=2003; citation_pages=3083-3099; citation_doi=10.1016/S0968-0896(03)00270-0; citation_id=CR41"/> <meta name="citation_reference" content="citation_journal_title=J. Chem. Soc., Perkin Trans.; citation_title=Structure–function studies on nucleoside antibiotic mureidomycin A: synthesis of 5′-functionalised uridine models; citation_author=C A Gentle, S A. Harrison, M Inukai, T D. H. Bugg; citation_volume=1; citation_publication_date=1999; citation_pages=1287-1294; citation_doi=10.1039/a901287g; citation_id=CR42"/> <meta name="citation_reference" content="citation_journal_title=Chem. Biol.; citation_title=Small-molecule inhibitors of protein-protein interactions: progressing toward the reality; citation_author=MR Arkin, Y Tang, JA Wells; citation_volume=21; citation_publication_date=2014; citation_pages=1102-1114; citation_doi=10.1016/j.chembiol.2014.09.001; citation_id=CR43"/> <meta name="citation_reference" content="citation_journal_title=Bioorg. Med Chem. Lett.; citation_title=Synthesis of the nucleoside moiety of liposidomycins: elucidation of the pharmacophore of this family of MraY inhibitors; citation_author=C Dini; citation_volume=10; citation_publication_date=2000; citation_pages=1839-1843; citation_doi=10.1016/S0960-894X(00)00349-8; citation_id=CR44"/> <meta name="citation_reference" content="citation_journal_title=Antimicrob. Agents Chemother.; citation_title=Activity of SQ641, a capuramycin analog, in a murine model of tuberculosis; citation_author=BV Nikonenko; citation_volume=53; citation_publication_date=2009; citation_pages=3138-3139; citation_doi=10.1128/AAC.00366-09; citation_id=CR45"/> <meta name="citation_reference" content="citation_journal_title=Antimicrob. Agents Chemother.; citation_title=Therapeutic efficacy of SQ641-NE against Mycobacterium tuberculosis; citation_author=B Nikonenko; citation_volume=58; citation_publication_date=2014; citation_pages=587-589; citation_doi=10.1128/AAC.01254-13; citation_id=CR46"/> <meta name="citation_reference" content="citation_journal_title=J. Antibiot. (Tokyo); citation_title=Discovery of a capuramycin analog that kills nonreplicating Mycobacterium tuberculosis and its synergistic effects with translocase I inhibitors; citation_author=S Siricilla, K Mitachi, B Wan, SG Franzblau, M Kurosu; citation_volume=68; citation_publication_date=2015; citation_pages=271-278; citation_doi=10.1038/ja.2014.133; citation_id=CR47"/> <meta name="citation_reference" content="citation_journal_title=J. Antimicrob. Chemother.; citation_title=Treatment of Clostridium difficile infection using SQ641, a capuramycin analogue, increases post-treatment survival and improves clinical measures of disease in a murine model; citation_author=JH Moore; citation_volume=71; citation_publication_date=2016; citation_pages=1300-1306; citation_doi=10.1093/jac/dkv479; citation_id=CR48"/> <meta name="citation_reference" content="citation_journal_title=J. Antibiot. (Tokyo); citation_title=New types of liposidomycins that inhibit bacterial peptidoglycan synthesis and are produced by Streptomyces. I. Producing organism and medium components; citation_author=K Kimura; citation_volume=51; citation_publication_date=1998; citation_pages=640-646; citation_doi=10.7164/antibiotics.51.640; citation_id=CR49"/> <meta name="citation_reference" content="citation_journal_title=J. Antibiot. (Tokyo); citation_title=New types of liposidomycins that inhibit bacterial peptidoglycan synthesis and are produced by Streptomyces. II. Isolation and structure elucidation; citation_author=K Kimura; citation_volume=51; citation_publication_date=1998; citation_pages=647-654; citation_doi=10.7164/antibiotics.51.647; citation_id=CR50"/> <meta name="citation_reference" content="citation_journal_title=J. Antibiot. (Tokyo); citation_title=New types of liposidomycins produced by Streptomyces that inhibit bacterial peptidoglycan synthesis. Structure elucidation of fatty acid components by tandem mass spectrometry; citation_author=Y Esumi; citation_volume=52; citation_publication_date=1999; citation_pages=281-287; citation_doi=10.7164/antibiotics.52.281; citation_id=CR51"/> <meta name="citation_reference" content="citation_journal_title=J. Antibiot. (Tokyo); citation_title=Selective inhibition of the bacterial peptidoglycan biosynthesis by the new types of liposidomycins; citation_author=K Kimura; citation_volume=51; citation_publication_date=1998; citation_pages=1099-1104; citation_doi=10.7164/antibiotics.51.1099; citation_id=CR52"/> <meta name="citation_reference" content="citation_journal_title=Nat. Prod. Rep.; citation_title=Recent advances in antimicrobial nucleoside antibiotics targeting cell wall biosynthesis; citation_author=K-i Kimura, TDH Bugg; citation_volume=20; citation_publication_date=2003; citation_pages=252-273; citation_doi=10.1039/b202149h; citation_id=CR53"/> <meta name="citation_reference" content="citation_journal_title=ACS Med. Chem. Lett.; citation_title=Synthesis and biological evaluation of muraymycin analogues active against anti-drug-resistant bacteria; citation_author=T Tanino; citation_volume=1; citation_publication_date=2010; citation_pages=258-262; citation_doi=10.1021/ml100057z; citation_id=CR54"/> <meta name="citation_reference" content="citation_journal_title=Biol. Crystallogr; citation_title=Xds. Acta Crystallogr D; citation_author=W Kabsch; citation_volume=66; citation_publication_date=2010; citation_pages=125-132; citation_doi=10.1107/S0907444909047337; citation_id=CR55"/> <meta name="citation_reference" content="citation_journal_title=Acta Crystallogr D. Biol. Crystallogr; citation_title=Clustering procedures for the optimal selection of data sets from multiple crystals in macromolecular crystallography; citation_author=J Foadi; citation_volume=69; citation_publication_date=2013; citation_pages=1617-1632; citation_doi=10.1107/S0907444913012274; citation_id=CR56"/> <meta name="citation_reference" content="Tickle, I. J. et al. STARANISO. Global Phasing, Inc. (2019). http://staraniso.globalphasing.org/cgi-bin/staraniso.cgi ."/> <meta name="citation_reference" content="citation_journal_title=J. Appl Crystallogr; citation_title=Phaser crystallographic software; citation_author=AJ McCoy; citation_volume=40; citation_publication_date=2007; citation_pages=658-674; citation_doi=10.1107/S0021889807021206; citation_id=CR58"/> <meta name="citation_reference" content="citation_journal_title=Acta Crystallogr. D Biol. Crystallogr.; citation_title=Features and development of Coot; citation_author=P Emsley, B Lohkamp, WG Scott, K Cowtan; citation_volume=66; citation_publication_date=2010; citation_pages=486-501; citation_doi=10.1107/S0907444910007493; citation_id=CR59"/> <meta name="citation_reference" content="citation_journal_title=Acta Crystallogr. D Biol. Crystallogr.; citation_title=Towards automated crystallographic structure refinement with phenix.refine; citation_author=PV Afonine; citation_volume=68; citation_publication_date=2012; citation_pages=352-367; citation_doi=10.1107/S0907444912001308; citation_id=CR60"/> <meta name="citation_reference" content="citation_journal_title=Acta Crystallogr. D Struct. Biol.; citation_title=Automated refinement of macromolecular structures at low resolution using prior information; citation_author=O Kovalevskiy, RA Nicholls, GN Murshudov; citation_volume=72; citation_publication_date=2016; citation_pages=1149-1161; citation_doi=10.1107/S2059798316014534; citation_id=CR61"/> <meta name="citation_reference" content="The PyMOL Molecular Graphics System. Version 2.0 Schrödinger, LLC."/> <meta name="citation_reference" content="citation_journal_title=Isr. J. Chem.; citation_title=ConSurf: using evolutionary data to raise testable hypotheses about protein function; citation_author=G Celniker; citation_volume=53; citation_publication_date=2013; citation_pages=199-206; citation_doi=10.1002/ijch.201200096; citation_id=CR63"/> <meta name="citation_reference" content="citation_journal_title=Sci. Rep.; citation_title=A rapid and efficient luminescence-based method for assaying phosphoglycosyltransferase enzymes; citation_author=D Das, MT Walvoort, V Lukose, B Imperiali; citation_volume=6; citation_publication_date=2016; citation_doi=10.1038/srep33412; citation_id=CR64"/> <meta name="citation_reference" content="citation_journal_title=Org. Lett.; citation_title=Concise synthesis of capuramycin; citation_author=M Kurosu, K Li, DC Crick; citation_volume=11; citation_publication_date=2009; citation_pages=2393-2396; citation_doi=10.1021/ol900458w; citation_id=CR65"/> <meta name="citation_author" content="Mashalidis, Ellene H."/> <meta name="citation_author_institution" content="Department of Biochemistry, Duke University Medical Center, Durham, USA"/> <meta name="citation_author" content="Kaeser, Benjamin"/> <meta name="citation_author_institution" content="Department of Biochemistry, Duke University Medical Center, Durham, USA"/> <meta name="citation_author" content="Terasawa, Yuma"/> <meta name="citation_author_institution" content="Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan"/> <meta name="citation_author" content="Katsuyama, Akira"/> <meta name="citation_author_institution" content="Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan"/> <meta name="citation_author" content="Kwon, Do-Yeon"/> <meta name="citation_author_institution" content="Department of Chemistry, Duke University, Durham, USA"/> <meta name="citation_author" content="Lee, Kiyoun"/> <meta name="citation_author_institution" content="Department of Chemistry, The Catholic University of Korea, Bucheon, Korea"/> <meta name="citation_author" content="Hong, Jiyong"/> <meta name="citation_author_institution" content="Department of Chemistry, Duke University, Durham, USA"/> <meta name="citation_author" content="Ichikawa, Satoshi"/> <meta name="citation_author_institution" content="Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan"/> <meta name="citation_author" content="Lee, Seok-Yong"/> <meta name="citation_author_institution" content="Department of Biochemistry, Duke University Medical Center, Durham, USA"/> <meta name="access_endpoint" content="https://www.nature.com/platform/readcube-access"/> <meta name="twitter:site" content="@NatureComms"/> <meta name="twitter:card" content="summary_large_image"/> <meta name="twitter:image:alt" content="Content cover image"/> <meta name="twitter:title" content="Chemical logic of MraY inhibition by antibacterial nucleoside natural products"/> <meta name="twitter:description" content="Nature Communications - Phospho-MurNAc-pentapeptide translocase (MraY) is a bacterial integral membrane enzyme that is essential for peptidoglycan biosynthesis. Here the authors present the crystal..."/> <meta name="twitter:image" content="https://media.springernature.com/full/springer-static/image/art%3A10.1038%2Fs41467-019-10957-9/MediaObjects/41467_2019_10957_Fig1_HTML.png"/> <meta property="og:url" content="https://www.nature.com/articles/s41467-019-10957-9"/> <meta property="og:type" content="article"/> <meta property="og:site_name" content="Nature"/> <meta property="og:title" content="Chemical logic of MraY inhibition by antibacterial nucleoside natural products - Nature Communications"/> <meta property="og:description" content="Phospho-MurNAc-pentapeptide translocase (MraY) is a bacterial integral membrane enzyme that is essential for peptidoglycan biosynthesis. Here the authors present the crystal structures of MraY from Aquifex aeolicus bound to caprazamycin, capuramycin and mureidomycin and discuss the implications for antibiotic development."/> <meta property="og:image" content="https://media.springernature.com/m685/springer-static/image/art%3A10.1038%2Fs41467-019-10957-9/MediaObjects/41467_2019_10957_Fig1_HTML.png"/> <script> window.eligibleForRa21 = 'false'; </script> </head> <body class="article-page"> <noscript><iframe src="https://www.googletagmanager.com/ns.html?id=GTM-MRVXSHQ" height="0" width="0" style="display:none;visibility:hidden"></iframe></noscript> <div class="position-relative cleared z-index-50 background-white" data-test="top-containers"> <a class="c-skip-link" href="#content">Skip to main content</a> <div class="c-grade-c-banner u-hide"> <div class="c-grade-c-banner__container"> <p>Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.</p> </div> </div> <div class="u-hide u-show-following-ad"></div> <aside class="c-ad c-ad--728x90"> <div class="c-ad__inner" data-container-type="banner-advert"> <p class="c-ad__label">Advertisement</p> <div id="div-gpt-ad-top-1" class="div-gpt-ad advert leaderboard js-ad text-center hide-print grade-c-hide" data-ad-type="top" data-test="top-ad" data-pa11y-ignore data-gpt data-gpt-unitpath="/285/nature_communications/article" data-gpt-sizes="728x90" data-gpt-targeting="type=article;pos=top;artid=s41467-019-10957-9;doi=10.1038/s41467-019-10957-9;techmeta=82,83;subjmeta=1172,1266,1290,22,326,45,535,607,631;kwrd=Antibiotics,Transferases,X-ray+crystallography"> <noscript> <a href="//pubads.g.doubleclick.net/gampad/jump?iu=/285/nature_communications/article&sz=728x90&c=-1367968756&t=pos%3Dtop%26type%3Darticle%26artid%3Ds41467-019-10957-9%26doi%3D10.1038/s41467-019-10957-9%26techmeta%3D82,83%26subjmeta%3D1172,1266,1290,22,326,45,535,607,631%26kwrd%3DAntibiotics,Transferases,X-ray+crystallography"> <img data-test="gpt-advert-fallback-img" src="//pubads.g.doubleclick.net/gampad/ad?iu=/285/nature_communications/article&sz=728x90&c=-1367968756&t=pos%3Dtop%26type%3Darticle%26artid%3Ds41467-019-10957-9%26doi%3D10.1038/s41467-019-10957-9%26techmeta%3D82,83%26subjmeta%3D1172,1266,1290,22,326,45,535,607,631%26kwrd%3DAntibiotics,Transferases,X-ray+crystallography" alt="Advertisement" width="728" height="90"></a> </noscript> </div> </div> </aside> <header class="c-header" id="header" data-header data-track-component="nature-150-split-header" style="border-color:#e63323"> <div class="c-header__row"> <div class="c-header__container"> <div class="c-header__split"> <div class="c-header__logo-container"> <a href="/ncomms" data-track="click" data-track-action="home" data-track-label="image"> <picture class="c-header__logo"> <source srcset="https://media.springernature.com/full/nature-cms/uploads/product/ncomms/header-03d2e325c0a02f6df509e5730e9be304.svg" media="(min-width: 875px)"> <img src="https://media.springernature.com/full/nature-cms/uploads/product/ncomms/header-7001f06bc3fe2437048388e9f2f44215.svg" height="32" alt="Nature Communications"> </picture> </a> </div> <ul class="c-header__menu c-header__menu--global"> <li class="c-header__item c-header__item--padding c-header__item--hide-md-max"> <a class="c-header__link" href="https://www.nature.com/siteindex" data-test="siteindex-link" data-track="click" data-track-action="open nature research index" data-track-label="link"> <span>View all journals</span> </a> </li> <li class="c-header__item c-header__item--padding c-header__item--pipe"> <a class="c-header__link c-header__link--search" href="#search-menu" data-header-expander data-test="search-link" data-track="click" data-track-action="open search tray" data-track-label="button"> <svg role="img" aria-hidden="true" focusable="false" height="22" width="22" viewBox="0 0 18 18" xmlns="http://www.w3.org/2000/svg"><path d="M16.48 15.455c.283.282.29.749.007 1.032a.738.738 0 01-1.032-.007l-3.045-3.044a7 7 0 111.026-1.026zM8 14A6 6 0 108 2a6 6 0 000 12z"/></svg><span>Search</span> </a> </li> <li class="c-header__item c-header__item--padding c-header__item--snid-account-widget c-header__item--pipe"> <a class="c-header__link eds-c-header__link" id="identity-account-widget" href='https://idp.nature.com/auth/personal/springernature?redirect_uri=https://www.nature.com/articles/s41467-019-10957-9?error=cookies_not_supported&code=b4a9cad7-676f-4114-8528-88c2fe1d56e7'><span class="eds-c-header__widget-fragment-title">Log in</span></a> </li> </ul> </div> </div> </div> <div class="c-header__row"> <div class="c-header__container" data-test="navigation-row"> <div class="c-header__split"> <ul class="c-header__menu c-header__menu--journal"> <li class="c-header__item c-header__item--dropdown-menu" data-test="explore-content-button"> <a href="#explore" class="c-header__link" data-header-expander data-test="menu-button--explore" data-track="click" data-track-action="open explore expander" data-track-label="button"> <span><span class="c-header__show-text">Explore</span> content</span><svg role="img" aria-hidden="true" focusable="false" height="16" viewBox="0 0 16 16" width="16" xmlns="http://www.w3.org/2000/svg"><path d="m5.58578644 3-3.29289322-3.29289322c-.39052429-.39052429-.39052429-1.02368927 0-1.41421356s1.02368927-.39052429 1.41421356 0l4 4c.39052429.39052429.39052429 1.02368927 0 1.41421356l-4 4c-.39052429.39052429-1.02368927.39052429-1.41421356 0s-.39052429-1.02368927 0-1.41421356z" transform="matrix(0 1 -1 0 11 3)"/></svg> </a> </li> <li class="c-header__item c-header__item--dropdown-menu"> <a href="#about-the-journal" class="c-header__link" data-header-expander data-test="menu-button--about-the-journal" data-track="click" data-track-action="open about the journal expander" data-track-label="button"> <span>About <span class="c-header__show-text">the journal</span></span><svg role="img" aria-hidden="true" focusable="false" height="16" viewBox="0 0 16 16" width="16" xmlns="http://www.w3.org/2000/svg"><path d="m5.58578644 3-3.29289322-3.29289322c-.39052429-.39052429-.39052429-1.02368927 0-1.41421356s1.02368927-.39052429 1.41421356 0l4 4c.39052429.39052429.39052429 1.02368927 0 1.41421356l-4 4c-.39052429.39052429-1.02368927.39052429-1.41421356 0s-.39052429-1.02368927 0-1.41421356z" transform="matrix(0 1 -1 0 11 3)"/></svg> </a> </li> <li class="c-header__item c-header__item--dropdown-menu" data-test="publish-with-us-button"> <a href="#publish-with-us" class="c-header__link c-header__link--dropdown-menu" data-header-expander data-test="menu-button--publish" data-track="click" data-track-action="open publish with us expander" data-track-label="button"> <span>Publish <span class="c-header__show-text">with us</span></span><svg role="img" aria-hidden="true" focusable="false" height="16" viewBox="0 0 16 16" width="16" xmlns="http://www.w3.org/2000/svg"><path d="m5.58578644 3-3.29289322-3.29289322c-.39052429-.39052429-.39052429-1.02368927 0-1.41421356s1.02368927-.39052429 1.41421356 0l4 4c.39052429.39052429.39052429 1.02368927 0 1.41421356l-4 4c-.39052429.39052429-1.02368927.39052429-1.41421356 0s-.39052429-1.02368927 0-1.41421356z" transform="matrix(0 1 -1 0 11 3)"/></svg> </a> </li> </ul> <ul class="c-header__menu c-header__menu--hide-lg-max"> <li class="c-header__item"> <a class="c-header__link" href="https://idp.nature.com/auth/personal/springernature?redirect_uri=https%3A%2F%2Fwww.nature.com%2Fmy-account%2Falerts%2Fsubscribe-journal%3Flist-id%3D264%26journal-link%3Dhttps%253A%252F%252Fwww.nature.com%252Fncomms%252F" rel="nofollow" data-track="click" data-track-action="Sign up for alerts" data-track-label="link (desktop site header)" data-track-external> <span>Sign up for alerts</span><svg role="img" aria-hidden="true" focusable="false" height="18" viewBox="0 0 18 18" width="18" xmlns="http://www.w3.org/2000/svg"><path d="m4 10h2.5c.27614237 0 .5.2238576.5.5s-.22385763.5-.5.5h-3.08578644l-1.12132034 1.1213203c-.18753638.1875364-.29289322.4418903-.29289322.7071068v.1715729h14v-.1715729c0-.2652165-.1053568-.5195704-.2928932-.7071068l-1.7071068-1.7071067v-3.4142136c0-2.76142375-2.2385763-5-5-5-2.76142375 0-5 2.23857625-5 5zm3 4c0 1.1045695.8954305 2 2 2s2-.8954305 2-2zm-5 0c-.55228475 0-1-.4477153-1-1v-.1715729c0-.530433.21071368-1.0391408.58578644-1.4142135l1.41421356-1.4142136v-3c0-3.3137085 2.6862915-6 6-6s6 2.6862915 6 6v3l1.4142136 1.4142136c.3750727.3750727.5857864.8837805.5857864 1.4142135v.1715729c0 .5522847-.4477153 1-1 1h-4c0 1.6568542-1.3431458 3-3 3-1.65685425 0-3-1.3431458-3-3z" fill="#222"/></svg> </a> </li> <li class="c-header__item c-header__item--pipe"> <a class="c-header__link" href="https://www.nature.com/ncomms.rss" data-track="click" data-track-action="rss feed" data-track-label="link"> <span>RSS feed</span> </a> </li> </ul> </div> </div> </div> </header> <nav class="u-mb-16" aria-label="breadcrumbs"> <div class="u-container"> <ol class="c-breadcrumbs" itemscope itemtype="https://schema.org/BreadcrumbList"> <li class="c-breadcrumbs__item" id="breadcrumb0" itemprop="itemListElement" itemscope itemtype="https://schema.org/ListItem"><a class="c-breadcrumbs__link" href="/" itemprop="item" data-track="click" data-track-action="breadcrumb" data-track-category="header" data-track-label="link:nature"><span itemprop="name">nature</span></a><meta itemprop="position" content="1"> <svg class="c-breadcrumbs__chevron" role="img" aria-hidden="true" focusable="false" height="10" viewBox="0 0 10 10" width="10" xmlns="http://www.w3.org/2000/svg"> <path d="m5.96738168 4.70639573 2.39518594-2.41447274c.37913917-.38219212.98637524-.38972225 1.35419292-.01894278.37750606.38054586.37784436.99719163-.00013556 1.37821513l-4.03074001 4.06319683c-.37758093.38062133-.98937525.38100976-1.367372-.00003075l-4.03091981-4.06337806c-.37759778-.38063832-.38381821-.99150444-.01600053-1.3622839.37750607-.38054587.98772445-.38240057 1.37006824.00302197l2.39538588 2.4146743.96295325.98624457z" fill="#666" fill-rule="evenodd" transform="matrix(0 -1 1 0 0 10)"/> </svg> </li><li class="c-breadcrumbs__item" id="breadcrumb1" itemprop="itemListElement" itemscope itemtype="https://schema.org/ListItem"><a class="c-breadcrumbs__link" href="/ncomms" itemprop="item" data-track="click" data-track-action="breadcrumb" data-track-category="header" data-track-label="link:nature communications"><span itemprop="name">nature communications</span></a><meta itemprop="position" content="2"> <svg class="c-breadcrumbs__chevron" role="img" aria-hidden="true" focusable="false" height="10" viewBox="0 0 10 10" width="10" xmlns="http://www.w3.org/2000/svg"> <path d="m5.96738168 4.70639573 2.39518594-2.41447274c.37913917-.38219212.98637524-.38972225 1.35419292-.01894278.37750606.38054586.37784436.99719163-.00013556 1.37821513l-4.03074001 4.06319683c-.37758093.38062133-.98937525.38100976-1.367372-.00003075l-4.03091981-4.06337806c-.37759778-.38063832-.38381821-.99150444-.01600053-1.3622839.37750607-.38054587.98772445-.38240057 1.37006824.00302197l2.39538588 2.4146743.96295325.98624457z" fill="#666" fill-rule="evenodd" transform="matrix(0 -1 1 0 0 10)"/> </svg> </li><li class="c-breadcrumbs__item" id="breadcrumb2" itemprop="itemListElement" itemscope itemtype="https://schema.org/ListItem"><a class="c-breadcrumbs__link" href="/ncomms/articles?type=article" itemprop="item" data-track="click" data-track-action="breadcrumb" data-track-category="header" data-track-label="link:articles"><span itemprop="name">articles</span></a><meta itemprop="position" content="3"> <svg class="c-breadcrumbs__chevron" role="img" aria-hidden="true" focusable="false" height="10" viewBox="0 0 10 10" width="10" xmlns="http://www.w3.org/2000/svg"> <path d="m5.96738168 4.70639573 2.39518594-2.41447274c.37913917-.38219212.98637524-.38972225 1.35419292-.01894278.37750606.38054586.37784436.99719163-.00013556 1.37821513l-4.03074001 4.06319683c-.37758093.38062133-.98937525.38100976-1.367372-.00003075l-4.03091981-4.06337806c-.37759778-.38063832-.38381821-.99150444-.01600053-1.3622839.37750607-.38054587.98772445-.38240057 1.37006824.00302197l2.39538588 2.4146743.96295325.98624457z" fill="#666" fill-rule="evenodd" transform="matrix(0 -1 1 0 0 10)"/> </svg> </li><li class="c-breadcrumbs__item" id="breadcrumb3" itemprop="itemListElement" itemscope itemtype="https://schema.org/ListItem"> <span itemprop="name">article</span><meta itemprop="position" content="4"></li> </ol> </div> </nav> </div> <div class="u-container u-mt-32 u-mb-32 u-clearfix" id="content" data-component="article-container" data-container-type="article"> <main class="c-article-main-column u-float-left js-main-column" data-track-component="article body"> <div class="c-context-bar u-hide" data-test="context-bar" data-context-bar aria-hidden="true"> <div class="c-context-bar__container u-container" data-track-context="sticky banner"> <div class="c-context-bar__title"> Chemical logic of MraY inhibition by antibacterial nucleoside natural products </div> <div class="c-pdf-download u-clear-both js-pdf-download"> <a href="/articles/s41467-019-10957-9.pdf" class="u-button u-button--full-width u-button--primary u-justify-content-space-between c-pdf-download__link" data-article-pdf="true" data-readcube-pdf-url="true" data-test="download-pdf" data-draft-ignore="true" data-track="content_download" data-track-type="article pdf download" data-track-action="download pdf" data-track-label="link" data-track-external download> <span class="c-pdf-download__text">Download PDF</span> <svg aria-hidden="true" focusable="false" width="16" height="16" class="u-icon"><use xlink:href="#icon-download"/></svg> </a> </div> </div> </div> <article lang="en"> <div class="c-pdf-button__container u-mb-16 u-hide-at-lg js-context-bar-sticky-point-mobile"> <div class="c-pdf-container" data-track-context="article body"> <div class="c-pdf-download u-clear-both js-pdf-download"> <a href="/articles/s41467-019-10957-9.pdf" class="u-button u-button--full-width u-button--primary u-justify-content-space-between c-pdf-download__link" data-article-pdf="true" data-readcube-pdf-url="true" data-test="download-pdf" data-draft-ignore="true" data-track="content_download" data-track-type="article pdf download" data-track-action="download pdf" data-track-label="link" data-track-external download> <span class="c-pdf-download__text">Download PDF</span> <svg aria-hidden="true" focusable="false" width="16" height="16" class="u-icon"><use xlink:href="#icon-download"/></svg> </a> </div> </div> </div> <div class="c-article-header"> <header> <ul class="c-article-identifiers" data-test="article-identifier"> <li class="c-article-identifiers__item" data-test="article-category">Article</li> <li class="c-article-identifiers__item"> <a href="https://www.springernature.com/gp/open-research/about/the-fundamentals-of-open-access-and-open-research" data-track="click" data-track-action="open access" data-track-label="link" class="u-color-open-access" data-test="open-access">Open access</a> </li> <li class="c-article-identifiers__item">Published: <time datetime="2019-07-02">02 July 2019</time></li> </ul> <h1 class="c-article-title" data-test="article-title" data-article-title="">Chemical logic of MraY inhibition by antibacterial nucleoside natural products</h1> <ul class="c-article-author-list c-article-author-list--short" data-test="authors-list" data-component-authors-activator="authors-list"><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Ellene_H_-Mashalidis-Aff1" data-author-popup="auth-Ellene_H_-Mashalidis-Aff1" data-author-search="Mashalidis, Ellene H.">Ellene H. Mashalidis</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup>, </li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Benjamin-Kaeser-Aff1" data-author-popup="auth-Benjamin-Kaeser-Aff1" data-author-search="Kaeser, Benjamin">Benjamin Kaeser</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Yuma-Terasawa-Aff2" data-author-popup="auth-Yuma-Terasawa-Aff2" data-author-search="Terasawa, Yuma">Yuma Terasawa</a><sup class="u-js-hide"><a href="#Aff2">2</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Akira-Katsuyama-Aff2" data-author-popup="auth-Akira-Katsuyama-Aff2" data-author-search="Katsuyama, Akira">Akira Katsuyama</a><span class="u-js-hide"> <a class="js-orcid" href="http://orcid.org/0000-0002-4062-5561"><span class="u-visually-hidden">ORCID: </span>orcid.org/0000-0002-4062-5561</a></span><sup class="u-js-hide"><a href="#Aff2">2</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Do_Yeon-Kwon-Aff3" data-author-popup="auth-Do_Yeon-Kwon-Aff3" data-author-search="Kwon, Do-Yeon">Do-Yeon Kwon</a><sup class="u-js-hide"><a href="#Aff3">3</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Kiyoun-Lee-Aff4" data-author-popup="auth-Kiyoun-Lee-Aff4" data-author-search="Lee, Kiyoun">Kiyoun Lee</a><sup class="u-js-hide"><a href="#Aff4">4</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Jiyong-Hong-Aff3" data-author-popup="auth-Jiyong-Hong-Aff3" data-author-search="Hong, Jiyong">Jiyong Hong</a><span class="u-js-hide"> <a class="js-orcid" href="http://orcid.org/0000-0002-5253-0949"><span class="u-visually-hidden">ORCID: </span>orcid.org/0000-0002-5253-0949</a></span><sup class="u-js-hide"><a href="#Aff3">3</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Satoshi-Ichikawa-Aff2" data-author-popup="auth-Satoshi-Ichikawa-Aff2" data-author-search="Ichikawa, Satoshi">Satoshi Ichikawa</a><sup class="u-js-hide"><a href="#Aff2">2</a></sup> & </li><li class="c-article-author-list__show-more" aria-label="Show all 9 authors for this article" title="Show all 9 authors for this article">…</li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Seok_Yong-Lee-Aff1" data-author-popup="auth-Seok_Yong-Lee-Aff1" data-author-search="Lee, Seok-Yong" data-corresp-id="c1">Seok-Yong Lee<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-mail-medium"></use></svg></a><span class="u-js-hide"> <a class="js-orcid" href="http://orcid.org/0000-0002-0662-9921"><span class="u-visually-hidden">ORCID: </span>orcid.org/0000-0002-0662-9921</a></span><sup class="u-js-hide"><a href="#Aff1">1</a></sup> </li></ul><button aria-expanded="false" class="c-article-author-list__button"><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-down-medium"></use></svg><span>Show authors</span></button> <p class="c-article-info-details" data-container-section="info"> <a data-test="journal-link" href="/ncomms" data-track="click" data-track-action="journal homepage" data-track-category="article body" data-track-label="link"><i data-test="journal-title">Nature Communications</i></a> <b data-test="journal-volume"><span class="u-visually-hidden">volume</span> 10</b>, Article number: <span data-test="article-number">2917</span> (<span data-test="article-publication-year">2019</span>) <a href="#citeas" class="c-article-info-details__cite-as u-hide-print" data-track="click" data-track-action="cite this article" data-track-label="link">Cite this article</a> </p> <div class="c-article-metrics-bar__wrapper u-clear-both"> <ul class="c-article-metrics-bar u-list-reset"> <li class=" c-article-metrics-bar__item" data-test="access-count"> <p class="c-article-metrics-bar__count">8031 <span class="c-article-metrics-bar__label">Accesses</span></p> </li> <li class="c-article-metrics-bar__item" data-test="altmetric-score"> <p class="c-article-metrics-bar__count">41 <span class="c-article-metrics-bar__label">Altmetric</span></p> </li> <li class="c-article-metrics-bar__item"> <p class="c-article-metrics-bar__details"><a href="/articles/s41467-019-10957-9/metrics" data-track="click" data-track-action="view metrics" data-track-label="link" rel="nofollow">Metrics <span class="u-visually-hidden">details</span></a></p> </li> </ul> </div> </header> <div class="u-js-hide" data-component="article-subject-links"> <h3 class="c-article__sub-heading">Subjects</h3> <ul class="c-article-subject-list"> <li class="c-article-subject-list__subject"><a href="/subjects/antibiotics" data-track="click" data-track-action="view subject" data-track-label="link">Antibiotics</a></li><li class="c-article-subject-list__subject"><a href="/subjects/transferases" data-track="click" data-track-action="view subject" data-track-label="link">Transferases</a></li><li class="c-article-subject-list__subject"><a href="/subjects/x-ray-crystallography" data-track="click" data-track-action="view subject" data-track-label="link">X-ray crystallography</a></li> </ul> </div> </div> <div class="c-article-body"> <section aria-labelledby="Abs1" data-title="Abstract" lang="en"><div class="c-article-section" id="Abs1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Abs1">Abstract</h2><div class="c-article-section__content" id="Abs1-content"><p>Novel antibacterial agents are needed to address the emergence of global antibiotic resistance. MraY is a promising candidate for antibiotic development because it is the target of five classes of naturally occurring nucleoside inhibitors with potent antibacterial activity. Although these natural products share a common uridine moiety, their core structures vary substantially and they exhibit different activity profiles. An incomplete understanding of the structural and mechanistic basis of MraY inhibition has hindered the translation of these compounds to the clinic. Here we present crystal structures of MraY in complex with representative members of the liposidomycin/caprazamycin, capuramycin, and mureidomycin classes of nucleoside inhibitors. Our structures reveal cryptic druggable hot spots in the shallow inhibitor binding site of MraY that were not previously appreciated. Structural analyses of nucleoside inhibitor binding provide insights into the chemical logic of MraY inhibition, which can guide novel approaches to MraY-targeted antibiotic design.</p></div></div></section> <noscript> </noscript> <section aria-labelledby="inline-recommendations" data-title="Inline Recommendations" class="c-article-recommendations" data-track-component="inline-recommendations"> <h3 class="c-article-recommendations-title" id="inline-recommendations">Similar content being viewed by others</h3> <div class="c-article-recommendations-list"> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1038%2Fs41467-022-35227-z/MediaObjects/41467_2022_35227_Fig1_HTML.png" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://www.nature.com/articles/s41467-022-35227-z?fromPaywallRec=false" data-track="select_recommendations_1" data-track-context="inline recommendations" data-track-action="click recommendations inline - 1" data-track-label="10.1038/s41467-022-35227-z">Synthesis of macrocyclic nucleoside antibacterials and their interactions with MraY </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__access-type">Open access</span> <span class="c-article-meta-recommendations__date">20 December 2022</span> </div> </div> </article> </div> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1038%2Fs41586-024-07530-w/MediaObjects/41586_2024_7530_Fig1_HTML.png" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://www.nature.com/articles/s41586-024-07530-w?fromPaywallRec=false" data-track="select_recommendations_2" data-track-context="inline recommendations" data-track-action="click recommendations inline - 2" data-track-label="10.1038/s41586-024-07530-w">Sophisticated natural products as antibiotics </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__date">31 July 2024</span> </div> </div> </article> </div> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1038%2Fs41421-024-00702-y/MediaObjects/41421_2024_702_Fig1_HTML.png" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://www.nature.com/articles/s41421-024-00702-y?fromPaywallRec=false" data-track="select_recommendations_3" data-track-context="inline recommendations" data-track-action="click recommendations inline - 3" data-track-label="10.1038/s41421-024-00702-y">Synthetic macrolides overcoming MLS<sub>B</sub>K-resistant pathogens </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__access-type">Open access</span> <span class="c-article-meta-recommendations__date">11 July 2024</span> </div> </div> </article> </div> </div> </section> <script> window.dataLayer = window.dataLayer || []; window.dataLayer.push({ recommendations: { recommender: 'semantic', model: 'specter', policy_id: 'NA', timestamp: 1732662429, embedded_user: 'null' } }); </script> <div class="main-content"> <section data-title="Introduction"><div class="c-article-section" id="Sec1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec1">Introduction</h2><div class="c-article-section__content" id="Sec1-content"><p>Drug-resistant bacterial infections have claimed the lives of millions of people worldwide<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Tackling Drug-Resistant infections Globally: Final Report and Recommendations. Rev. Antimicrob. Resist. (2016). 
 https://amrreview.org/
 
 ." href="/articles/s41467-019-10957-9#ref-CR1" id="ref-link-section-d35905315e458">1</a></sup>, underscoring an urgent need for the development of antibacterial compounds with novel mechanisms of action. Peptidoglycan biosynthesis is a pathway rich in antibiotic targets, including the penicillin-binding proteins, which are implicated in resistance mechanisms widely documented and studied<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Blair, J. M., Webber, M. A., Baylay, A. J., Ogbolu, D. O. & Piddock, L. J. Molecular mechanisms of antibiotic resistance. Nat. Rev. Microbiol 13, 42–51 (2015)." href="/articles/s41467-019-10957-9#ref-CR2" id="ref-link-section-d35905315e462">2</a></sup>. An attractive alternative and underexplored target in peptidoglycan biosynthesis is phospho-MurNAc-pentapeptide translocase (MraY), which is an essential integral membrane enzyme that catalyzes the first membrane-associated and committed step of peptidoglycan formation<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Hering, J., Dunevall, E., Ek, M. & Branden, G. Structural basis for selective inhibition of antibacterial target MraY, a membrane-bound enzyme involved in peptidoglycan synthesis. Drug Discov. Today 23, 1426–1435 (2018)." href="#ref-CR3" id="ref-link-section-d35905315e466">3</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Koppermann, S. & Ducho, C. Natural Products at Work: structural Insights into Inhibition of the Bacterial Membrane Protein MraY. Angew. Chem. Int. Ed. Engl. 55, 11722–11724 (2016)." href="#ref-CR4" id="ref-link-section-d35905315e466_1">4</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Koppermann, S. et al. Insights into the target interaction of naturally occurring muraymycin nucleoside antibiotics. ChemMedChem 13, 779–784 (2018)." href="/articles/s41467-019-10957-9#ref-CR5" id="ref-link-section-d35905315e469">5</a></sup>. MraY transfers phospho-MurNAc-pentapeptide from the hydrophilic substrate uridine diphosphate-MurNAc-pentapeptide (UM5A), to the lipid carrier undecaprenyl phosphate (C<sub>55</sub>-P) in the presence of a Mg<sup>2+</sup> cofactor. The resulting product is Lipid I, an intermediate in peptidoglycan biosynthesis (Supplementary Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM1">1a</a>).</p><p>MraY is the target of five classes of natural product nucleoside inhibitors isolated from <i>Streptomyces</i> species with promising activity against pathogenic bacteria: the liposidomycins/caprazamycins, capuramycins, mureidomycins, muraymycins, and tunicamycins. Each MraY inhibitor contains a uridine moiety, but they otherwise differ in their core chemical structures. Nucleoside natural product inhibitors exhibit differing antibacterial activity, structure-activity-relationship (SAR) profiles<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 6" title="Winn, M., Goss, R. J., Kimura, K. & Bugg, T. D. Antimicrobial nucleoside antibiotics targeting cell wall assembly: recent advances in structure-function studies and nucleoside biosynthesis. Nat. Prod. Rep. 27, 279–304 (2010)." href="/articles/s41467-019-10957-9#ref-CR6" id="ref-link-section-d35905315e487">6</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 7" title="Ichikawa, S., Yamaguchi, M. & Matsuda, A. Antibacterial nucleoside natural products inhibiting phospho-MurNAc-pentapeptide translocase; chemistry and structure-activity relationship. Curr. Med. Chem. 22, 3951–3979 (2015)." href="/articles/s41467-019-10957-9#ref-CR7" id="ref-link-section-d35905315e490">7</a></sup>, mechanisms of action<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 8" title="Brandish, P. E. et al. Modes of action of tunicamycin, liposidomycin B, and mureidomycin A: inhibition of phospho-N-acetylmuramyl-pentapeptide translocase from Escherichia coli. Antimicrob. Agents Chemother. 40, 1640–1644 (1996)." href="/articles/s41467-019-10957-9#ref-CR8" id="ref-link-section-d35905315e494">8</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 9" title="Muramatsu, Y., Ishii, M. M. & Inukai, M. Studies on novel bacterial translocase I inhibitors, A-500359s. II. Biological activities of A-500359 A, C., D. G. J. Antibiot. (Tokyo) 56, 253–258 (2003)." href="/articles/s41467-019-10957-9#ref-CR9" id="ref-link-section-d35905315e497">9</a></sup>, and inhibitor kinetics<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Brandish, P. E. et al. Modes of action of tunicamycin, liposidomycin B, and mureidomycin A: inhibition of phospho-N-acetylmuramyl-pentapeptide translocase from Escherichia coli. Antimicrob. Agents Chemother. 40, 1640–1644 (1996)." href="#ref-CR8" id="ref-link-section-d35905315e501">8</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Muramatsu, Y., Ishii, M. M. & Inukai, M. Studies on novel bacterial translocase I inhibitors, A-500359s. II. Biological activities of A-500359 A, C., D. G. J. Antibiot. (Tokyo) 56, 253–258 (2003)." href="#ref-CR9" id="ref-link-section-d35905315e501_1">9</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" title="Brandish, P. E. et al. Slow binding inhibition of phospho-N-acetylmuramyl-pentapeptide-translocase (Escherichia coli) by mureidomycin A. J. Biol. Chem. 271, 7609–7614 (1996)." href="/articles/s41467-019-10957-9#ref-CR10" id="ref-link-section-d35905315e504">10</a></sup> Tunicamycin inhibits both MraY and its eukaryotic paralog GlcNAc-1-P-transferase (GPT), leading to cytotoxicity<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="Duksin, D. & Mahoney, W. C. Relationship of the structure and biological activity of the natural homologues of tunicamycin. J. Biol. Chem. 257, 3105–3109 (1982)." href="/articles/s41467-019-10957-9#ref-CR11" id="ref-link-section-d35905315e508">11</a></sup>, but members of the other classes of nucleoside inhibitors are selective for bacterial MraY<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 9" title="Muramatsu, Y., Ishii, M. M. & Inukai, M. Studies on novel bacterial translocase I inhibitors, A-500359s. II. Biological activities of A-500359 A, C., D. G. J. Antibiot. (Tokyo) 56, 253–258 (2003)." href="/articles/s41467-019-10957-9#ref-CR9" id="ref-link-section-d35905315e513">9</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Inukai, M., Isono, F. & Takatsuki, A. Selective inhibition of the bacterial translocase reaction in peptidoglycan synthesis by mureidomycins. Antimicrob. Agents Chemother. 37, 980–983 (1993)." href="/articles/s41467-019-10957-9#ref-CR12" id="ref-link-section-d35905315e516">12</a></sup>. The mechanistic and structural basis for the distinct pharmacological properties observed among MraY-targeted nucleoside inhibitors is poorly understood.</p><p>Recent structures of tunicamycin bound to MraY<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 13" title="Hakulinen, J. K. et al. MraY-antibiotic complex reveals details of tunicamycin mode of action. Nat. Chem. Biol. 13, 265–267 (2017)." href="/articles/s41467-019-10957-9#ref-CR13" id="ref-link-section-d35905315e523">13</a></sup> and GPT<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 14" title="Yoo, J. et al. GlcNAc-1-P-transferase-tunicamycin complex structure reveals basis for inhibition of N-glycosylation. Nat. Struct. Mol. Biol. 25, 217–224 (2018)." href="/articles/s41467-019-10957-9#ref-CR14" id="ref-link-section-d35905315e527">14</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 15" title="Dong, Y. Y. et al. Structures of DPAGT1 explain glycosylation disease mechanisms and advance TB antibiotic design. Cell 175, 1045–1058 (2018). e1016." href="/articles/s41467-019-10957-9#ref-CR15" id="ref-link-section-d35905315e530">15</a></sup> show that the tunicamycin binding pocket is deep and occluded in GPT, while in MraY it is shallow and largely exposed to the cytosol. The MraY inhibitor binding site on the cytoplasmic face of MraY is unlike the large, deep, and enclosed binding pockets typically found in enzyme active sites<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 16" title="Perot, S., Sperandio, O., Miteva, M. A., Camproux, A. C. & Villoutreix, B. O. Druggable pockets and binding site centric chemical space: a paradigm shift in drug discovery. Drug Discov. Today 15, 656–667 (2010)." href="/articles/s41467-019-10957-9#ref-CR16" id="ref-link-section-d35905315e534">16</a></sup>. This observation raises an intriguing and important question: what strategy does nature employ to target the shallow cytosolic surface of MraY using nucleoside inhibitors with very different core chemical structures? One possibility is that the structural plasticity of MraY helps to accommodate structurally diverse inhibitors, as suggested by comparison of apoenzyme and muraymycin D2-bound MraY<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Chung, B. C. et al. Crystal structure of MraY, an essential membrane enzyme for bacterial cell wall synthesis. Science 341, 1012–1016 (2013)." href="/articles/s41467-019-10957-9#ref-CR17" id="ref-link-section-d35905315e538">17</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="Chung, B. C. et al. Structural insights into inhibition of lipid I production in bacterial cell wall synthesis. Nature 533, 557–560 (2016)." href="/articles/s41467-019-10957-9#ref-CR18" id="ref-link-section-d35905315e541">18</a></sup>. Alternatively, it is possible that the shallow surface of MraY contains many cryptic druggable sites, which can be exploited in different combinations by each nucleoside inhibitor. To address this question, we solved structures of MraY from <i>Aquifex aeolicus</i> (MraY<sub>AA</sub>) individually bound to carbacaprazamycin (a member of the caprazamycin class), capuramycin, and 3′-hydroxymureidomycin A (a ribose derivative of mureidomycin A). These three classes of nucleoside inhibitors are distinct in their chemical structures, mechanisms of inhibition, and antibacterial activity. For example, liposidomycin is competitive for C<sub>55</sub>-P, the lipid carrier substrate of MraY<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 8" title="Brandish, P. E. et al. Modes of action of tunicamycin, liposidomycin B, and mureidomycin A: inhibition of phospho-N-acetylmuramyl-pentapeptide translocase from Escherichia coli. Antimicrob. Agents Chemother. 40, 1640–1644 (1996)." href="/articles/s41467-019-10957-9#ref-CR8" id="ref-link-section-d35905315e553">8</a></sup>, while capuramycin is noncompetitive for C<sub>55</sub>-P and exhibits mixed type inhibition with respect to UM5A<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 9" title="Muramatsu, Y., Ishii, M. M. & Inukai, M. Studies on novel bacterial translocase I inhibitors, A-500359s. II. Biological activities of A-500359 A, C., D. G. J. Antibiot. (Tokyo) 56, 253–258 (2003)." href="/articles/s41467-019-10957-9#ref-CR9" id="ref-link-section-d35905315e559">9</a></sup>. The liposidomycins/caprazamycins demonstrate potent antibacterial activity against Gram-positive bacteria, mycobacteria, and various drug-resistant bacterial strains, including MRSA and VRE<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Hirano, S., Ichikawa, S. & Matsuda, A. Synthesis of caprazamycin analogues and their structure–activity relationship for antibacterial activity. J. Org. Chem. 73, 569–577 (2008)." href="/articles/s41467-019-10957-9#ref-CR19" id="ref-link-section-d35905315e563">19</a></sup>. Mureidomycin and its analogs appear to have a narrower spectrum of activity, primarily against <i>Pseudomonas</i> species<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Isono, F., Katayama, T., Inukai, M., Haneishi, T. & Mureidomycins, A.-D. novel peptidylnucleoside antibiotics with spheroplast forming activity. III. Biological properties. J. Antibiot. (Tokyo) 42, 674–679 (1989)." href="/articles/s41467-019-10957-9#ref-CR20" id="ref-link-section-d35905315e571">20</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 21" title="Isono, F., Kodama, K. & Inukai, M. Susceptibility of Pseudomonas species to the novel antibiotics mureidomycins. Antimicrob. Agents Chemother. 36, 1024–1027 (1992)." href="/articles/s41467-019-10957-9#ref-CR21" id="ref-link-section-d35905315e574">21</a></sup>, while the capuramycins are particularly effective against mycobacteria<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 22" title="Hotoda, H. et al. Synthesis and antimycobacterial activity of capuramycin analogues. Part 1: substitution of the azepan-2-one moiety of capuramycin. Bioorg. Med. Chem. Lett. 13, 2829–2832 (2003)." href="/articles/s41467-019-10957-9#ref-CR22" id="ref-link-section-d35905315e578">22</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 23" title="Hotoda, H. et al. Synthesis and antimycobacterial activity of capuramycin analogues. Part 2: acylated derivatives of capuramycin-related compounds. Bioorg. Med. Chem. Lett. 13, 2833–2836 (2003)." href="/articles/s41467-019-10957-9#ref-CR23" id="ref-link-section-d35905315e581">23</a></sup>; capuramycin analog SQ641 kills <i>Mycobacterium tuberculosis</i> faster than existing antitubercular drugs<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 24" title="Reddy, V. M., Einck, L. & Nacy, C. A. In vitro antimycobacterial activities of capuramycin analogues. Antimicrob. Agents Chemother. 52, 719–721 (2008)." href="/articles/s41467-019-10957-9#ref-CR24" id="ref-link-section-d35905315e588">24</a></sup>.</p><p>Our structures cover the chemical space sampled by MraY natural product inhibitors, revealing that they occupy both overlapping and unique sites on the cytoplasmic surface of MraY. This region of MraY is highly conserved among Gram-positive and Gram-negative bacteria, with 34 invariant amino acid residues comprising the active site<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Chung, B. C. et al. Crystal structure of MraY, an essential membrane enzyme for bacterial cell wall synthesis. Science 341, 1012–1016 (2013)." href="/articles/s41467-019-10957-9#ref-CR17" id="ref-link-section-d35905315e595">17</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="Chung, B. C. et al. Structural insights into inhibition of lipid I production in bacterial cell wall synthesis. Nature 533, 557–560 (2016)." href="/articles/s41467-019-10957-9#ref-CR18" id="ref-link-section-d35905315e598">18</a></sup>. Therefore, our crystal structures collectively serve as a generalizable MraY structural model by which nucleoside inhibitor SAR data can be analyzed and understood in order to achieve a comprehensive picture of MraY inhibition.</p></div></div></section><section data-title="Results"><div class="c-article-section" id="Sec2-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec2">Results</h2><div class="c-article-section__content" id="Sec2-content"><h3 class="c-article__sub-heading" id="Sec3">Crystal structures of MraY bound to nucleoside inhibitors</h3><p>We previously identified a biochemically stable ortholog of MraY from thermophile <i>Aquifex aeolicus</i> (MraY<sub>AA</sub>), with which we obtained crystal structures of MraY in its apoenzyme form<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Chung, B. C. et al. Crystal structure of MraY, an essential membrane enzyme for bacterial cell wall synthesis. Science 341, 1012–1016 (2013)." href="/articles/s41467-019-10957-9#ref-CR17" id="ref-link-section-d35905315e619">17</a></sup> as well as bound to muraymycin D2<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="Chung, B. C. et al. Structural insights into inhibition of lipid I production in bacterial cell wall synthesis. Nature 533, 557–560 (2016)." href="/articles/s41467-019-10957-9#ref-CR18" id="ref-link-section-d35905315e623">18</a></sup>. MraY<sub>AA</sub> is a good model with which to study MraY activity and inhibition because it recognizes the same substrates and catalyzes the same enzymatic reaction as do pathogenic Gram-positive and Gram-negative bacteria<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Chung, B. C. et al. Crystal structure of MraY, an essential membrane enzyme for bacterial cell wall synthesis. Science 341, 1012–1016 (2013)." href="/articles/s41467-019-10957-9#ref-CR17" id="ref-link-section-d35905315e630">17</a></sup>. MraY<sub>AA</sub> enzymatic activity is potently inhibited by carbacaprazamycin, capuramycin, and 3′-hydroxymureidomycin A with IC<sub>50</sub> values of 104 nM, 185 nM, and 52 nM, respectively (Supplementary Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM1">1b</a>), as well as by muraymycin D2<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="Chung, B. C. et al. Structural insights into inhibition of lipid I production in bacterial cell wall synthesis. Nature 533, 557–560 (2016)." href="/articles/s41467-019-10957-9#ref-CR18" id="ref-link-section-d35905315e641">18</a></sup> and tunicamycin<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 14" title="Yoo, J. et al. GlcNAc-1-P-transferase-tunicamycin complex structure reveals basis for inhibition of N-glycosylation. Nat. Struct. Mol. Biol. 25, 217–224 (2018)." href="/articles/s41467-019-10957-9#ref-CR14" id="ref-link-section-d35905315e645">14</a></sup>, which is comparable to the efficacy observed for MraY orthologs from pathogenic bacteria<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Brandish, P. E. et al. Modes of action of tunicamycin, liposidomycin B, and mureidomycin A: inhibition of phospho-N-acetylmuramyl-pentapeptide translocase from Escherichia coli. Antimicrob. Agents Chemother. 40, 1640–1644 (1996)." href="#ref-CR8" id="ref-link-section-d35905315e650">8</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Muramatsu, Y., Ishii, M. M. & Inukai, M. Studies on novel bacterial translocase I inhibitors, A-500359s. II. Biological activities of A-500359 A, C., D. G. J. Antibiot. (Tokyo) 56, 253–258 (2003)." href="#ref-CR9" id="ref-link-section-d35905315e650_1">9</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" title="Brandish, P. E. et al. Slow binding inhibition of phospho-N-acetylmuramyl-pentapeptide-translocase (Escherichia coli) by mureidomycin A. J. Biol. Chem. 271, 7609–7614 (1996)." href="/articles/s41467-019-10957-9#ref-CR10" id="ref-link-section-d35905315e653">10</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Inukai, M., Isono, F. & Takatsuki, A. Selective inhibition of the bacterial translocase reaction in peptidoglycan synthesis by mureidomycins. Antimicrob. Agents Chemother. 37, 980–983 (1993)." href="/articles/s41467-019-10957-9#ref-CR12" id="ref-link-section-d35905315e656">12</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Kimura, K.-i et al. Liposidomycin C inhibits phospho-N-acetylmuramyl-pentapeptide transferase in peptidoglycan synthesis of Escherichia coli Y-10. Agric. Biol. Chem. 53, 1811–1815 (1989)." href="#ref-CR25" id="ref-link-section-d35905315e659">25</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Ichikawa, S., Yamaguchi, M., Hsuan, L. S., Kato, Y. & Matsuda, A. Carbacaprazamycins: chemically stable analogues of the caprazamycin nucleoside antibiotics. ACS Infect. Dis. 1, 151–156 (2015)." href="#ref-CR26" id="ref-link-section-d35905315e659_1">26</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Isono, F. & Inukai, M. Mureidomycin A, a new inhibitor of bacterial peptidoglycan synthesis. Antimicrob. Agents Chemother. 35, 234–236 (1991)." href="#ref-CR27" id="ref-link-section-d35905315e659_2">27</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Tanino, T. et al. Mechanistic analysis of muraymycin analogues: a guide to the design of MraY inhibitors. J. Med. Chem. 54, 8421–8439 (2011)." href="#ref-CR28" id="ref-link-section-d35905315e659_3">28</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 29" title="Yamamoto, K., Katsuyama, A. & Ichikawa, S. Structural requirement of tunicamycin V for MraY inhibition. Bioorg. Med. Chem. Lett. 27, 1714–1719 (2019)." href="/articles/s41467-019-10957-9#ref-CR29" id="ref-link-section-d35905315e662">29</a></sup>. MraY<sub>AA</sub> was recalcitrant to crystallization in complex with members of the liposidomycin/caprazamycin, capuramycin, and mureidomycin classes of MraY inhibitors using previously employed methods. We addressed this challenge by obtaining different crystal forms of MraY<sub>AA</sub> in the presence of camelid single-chain antibodies called nanobodies. We identified several high-affinity MraY<sub>AA</sub> nanobodies that bind MraY<sub>AA</sub>, forming a complex that remained intact during size exclusion chromatography. One nanobody in particular, NB7, forms a tight complex with MraY<sub>AA</sub> (Supplementary Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM1">2a</a>), but does not interfere with MraY<sub>AA</sub> activity and inhibition (Supplementary Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM1">2b</a>). The ternary complex crystals of NB7, MraY<sub>AA</sub>, and either carbacaprazamycin, capuramycin, or 3′-hydroxymureidomycin A diffract to 2.95 Å, 3.62 Å, and 3.70 Å resolutions, respectively (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-019-10957-9#Fig1">1</a>). MraY<sub>AA</sub> crystallizes as a dimer, which is consistent with its oligomeric state<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Chung, B. C. et al. Crystal structure of MraY, an essential membrane enzyme for bacterial cell wall synthesis. Science 341, 1012–1016 (2013)." href="/articles/s41467-019-10957-9#ref-CR17" id="ref-link-section-d35905315e693">17</a></sup>. NB7 binds to each MraY<sub>AA</sub> protomer on its periplasmic face, away from the catalytic and inhibitor binding site (Supplementary Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM1">2c</a>). Phasing was obtained by molecular replacement and models were refined to good geometry and statistics (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/s41467-019-10957-9#Tab1">1</a>). Two MraY<sub>AA</sub>-NB7 dimer complexes are found in the asymmetric unit with inhibitor density strongest in one of the MraY<sub>AA</sub> protomers. The electron density maps for the structures were of high quality, allowing unambiguous placement of each inhibitor (Supplementary Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM1">3</a>).</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-1" data-title="Fig. 1"><figure><figcaption><b id="Fig1" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 1</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/s41467-019-10957-9/figures/1" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41467-019-10957-9/MediaObjects/41467_2019_10957_Fig1_HTML.png?as=webp"><img aria-describedby="Fig1" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41467-019-10957-9/MediaObjects/41467_2019_10957_Fig1_HTML.png" alt="figure 1" loading="lazy" width="685" height="429"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-1-desc"><p>X-ray crystal structures of MraY<sub>AA</sub> bound to nucleoside inhibitors. <b>a</b> Top: the MraY<sub>AA</sub>-carbacaprazamycin complex structure as viewed from the membrane, with one protomer shown in surface representation and one in cartoon. Carbacaprazamycin is shown in magenta. For simplicity, one protomer of MraY<sub>AA</sub> with bound carbacaprazamycin is shown from membrane and cytoplasmic views. <b>a</b> Bottom: chemical structure of carbacaprazamycin with its substructures labeled. (<b>b</b>, top) Membrane and cytoplasmic views of an MraY<sub>AA</sub> protomer bound to capuramycin (yellow). Loop E in is distorted and is represented by a dashed line. <b>b</b> Bottom: chemical structure of capuramycin. <b>c</b> Top: membrane and cytoplasmic views of an MraY<sub>AA</sub> protomer bound to 3′-hydroxymureidomycin A (green). <b>c</b> Bottom: chemical structure of 3′-hydroxymureidomycin A. Each MraY inhibitor binds distinctly to a site on the cytoplasmic face of MraY formed by TMs 5, 8, and 9b and Loops C, D, and E (labeled throughout)</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/s41467-019-10957-9/figures/1" data-track-dest="link:Figure1 Full size image" aria-label="Full size image figure 1" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><div class="c-article-table" data-test="inline-table" data-container-section="table" id="table-1"><figure><figcaption class="c-article-table__figcaption"><b id="Tab1" data-test="table-caption">Table 1 Data collection and refinement statistics</b></figcaption><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="table-link" data-track="click" data-track-action="view table" data-track-label="button" rel="nofollow" href="/articles/s41467-019-10957-9/tables/1" aria-label="Full size table 1"><span>Full size table</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>Each MraY inhibitor binds to a site on the cytoplasmic face of MraY, which is predominantly formed by TMs 5, 8, and 9b and Loops C, D, and E (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-019-10957-9#Fig1">1</a> and Supplementary Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM1">4</a>). Our three new crystal structures of MraY<sub>AA</sub> bound to carbacaprazamycin, capuramycin, and 3′-hydroxymureidomycin A reveal that the conformations of inhibitor-bound MraY structures are more similar to the MraY-muraymycin D2 complex than they are to the apoenzyme MraY structure (Supplementary Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM1">5</a>). The degree of TM9b bending and the structure of Loop E vary in each inhibitor-bound structure (Supplementary Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM1">5</a>).</p><h3 class="c-article__sub-heading" id="Sec4">The carbacaprazamycin binding site</h3><p>Carbacaprazamycin is a chemically stable analog of naturally occurring caprazamycin, which is a member of the lipopeptidyl class of MraY nucleoside inhibitors that includes the liposidomycins<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Ichikawa, S., Yamaguchi, M., Hsuan, L. S., Kato, Y. & Matsuda, A. Carbacaprazamycins: chemically stable analogues of the caprazamycin nucleoside antibiotics. ACS Infect. Dis. 1, 151–156 (2015)." href="/articles/s41467-019-10957-9#ref-CR26" id="ref-link-section-d35905315e1474">26</a></sup>. Carbacaprazamycin is comprised of uridine, 5-aminoribosyl, diazepanone, and aliphatic tail moieties (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-019-10957-9#Fig1">1a</a>). These moieties bind to pockets on the cytoplasmic face of MraY we term the uridine, uridine-adjacent, TM9b/Loop E and hydrophobic pockets (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-019-10957-9#Fig2">2a</a>). The uridine binding pocket in MraY is formed by amino acid residues in Loop C, including G194, L195, and D196, and is capped off by a π–π stacking interaction with F262 in Loop D (residue numbering for MraY<sub>AA</sub>) (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-019-10957-9#Fig2">2b</a>). An additional hydrogen bond with the uracil moiety is formed by K70. The orientation and binding mode of the carbacaprazamycin uridine moiety is very similar to that observed in the crystal structures of muraymycin D2 and tunicamycin bound to MraY<sub>AA</sub><sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="Chung, B. C. et al. Structural insights into inhibition of lipid I production in bacterial cell wall synthesis. Nature 533, 557–560 (2016)." href="/articles/s41467-019-10957-9#ref-CR18" id="ref-link-section-d35905315e1491">18</a></sup> and MraY from <i>Clostridium bolteae</i> (MraY<sub>CB</sub><sup>)<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 13" title="Hakulinen, J. K. et al. MraY-antibiotic complex reveals details of tunicamycin mode of action. Nat. Chem. Biol. 13, 265–267 (2017)." href="/articles/s41467-019-10957-9#ref-CR13" id="ref-link-section-d35905315e1500">13</a></sup>, respectively (Supplementary Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM1">4</a>). Next to the uridine binding site in MraY is a second binding pocket lined with amino acid residues T75, N190, D193, and G264, which we call the uridine-adjacent pocket. The 5-aminoribose moiety of carbacaprazamycin forms an extensive hydrogen bond network in the uridine-adjacent pocket (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-019-10957-9#Fig2">2b</a>), as does this moiety in muraymycin D2<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="Chung, B. C. et al. Structural insights into inhibition of lipid I production in bacterial cell wall synthesis. Nature 533, 557–560 (2016)." href="/articles/s41467-019-10957-9#ref-CR18" id="ref-link-section-d35905315e1511">18</a></sup>. The diazepanone ring system makes relatively few interactions with the protein. This observation is consistent with SAR studies demonstrating that the diazepanone ring can be broken with modest effect on activity<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Hirano, S., Ichikawa, S. & Matsuda, A. Design and synthesis of diketopiperazine and acyclic analogs related to the caprazamycins and liposidomycins as potential antibacterial agents. Bioorg. Med. Chem. 16, 428–436 (2008)." href="/articles/s41467-019-10957-9#ref-CR30" id="ref-link-section-d35905315e1515">30</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 31" title="Hirano, S., Ichikawa, S. & Matsuda, A. Structure-activity relationship of truncated analogs of caprazamycins as potential anti-tuberculosis agents. Bioorg. Med. Chem. 16, 5123–5133 (2008)." href="/articles/s41467-019-10957-9#ref-CR31" id="ref-link-section-d35905315e1518">31</a></sup>. However, the carboxylate group on the diazepanone forms a hydrogen bond with H325 in the Loop E helix (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-019-10957-9#Fig2">2b</a>).</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-2" data-title="Fig. 2"><figure><figcaption><b id="Fig2" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 2</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/s41467-019-10957-9/figures/2" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41467-019-10957-9/MediaObjects/41467_2019_10957_Fig2_HTML.png?as=webp"><img aria-describedby="Fig2" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41467-019-10957-9/MediaObjects/41467_2019_10957_Fig2_HTML.png" alt="figure 2" loading="lazy" width="685" height="342"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-2-desc"><p>Carbacaprazamycin binds to the hydrophobic groove in MraY<sub>AA</sub>. <b>a</b> The binding sites recognized by carbacaprazamycin (magenta) on the cytoplasmic side of MraY<sub>AA</sub> include the uridine (red), uridine-adjacent (lime green), TM9b/Loop E (purple), and hydrophobic (cyan) pockets. <b>b</b> A zoomed-in view of the carbacaprazamycin binding site in the same orientation as shown in <b>a</b>. Residues forming interactions with carbacaprazamycin are labeled and color-coded according to the binding pocket to which they belong. Hydrogen bonds are represented by dashed lines. <b>c</b> A view of the carbacaprazamycin binding site rotated 90° relative to the orientation shown in <b>a</b> to highlight the aliphatic tail binding site (cyan dashes lines). TMs (numbers) and Loops (letters) are labeled throughout</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/s41467-019-10957-9/figures/2" data-track-dest="link:Figure2 Full size image" aria-label="Full size image figure 2" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>Adjacent to the highly-charged nucleoside binding pocket on the cytoplasmic side of MraY is a long hydrophobic groove predominantly formed by TMs 5 and 9b leading into the plane of the membrane, which has been predicted to be the lipid carrier substrate C<sub>55</sub>-P binding site<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Chung, B. C. et al. Crystal structure of MraY, an essential membrane enzyme for bacterial cell wall synthesis. Science 341, 1012–1016 (2013)." href="/articles/s41467-019-10957-9#ref-CR17" id="ref-link-section-d35905315e1568">17</a></sup>. Two of the major nucleoside inhibitor classes, the liposidomycins and the tunicamycins, contain aliphatic moieties that are thought to compete with the lipid carrier substrate, C<sub>55</sub>-P<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 8" title="Brandish, P. E. et al. Modes of action of tunicamycin, liposidomycin B, and mureidomycin A: inhibition of phospho-N-acetylmuramyl-pentapeptide translocase from Escherichia coli. Antimicrob. Agents Chemother. 40, 1640–1644 (1996)." href="/articles/s41467-019-10957-9#ref-CR8" id="ref-link-section-d35905315e1574">8</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 9" title="Muramatsu, Y., Ishii, M. M. & Inukai, M. Studies on novel bacterial translocase I inhibitors, A-500359s. II. Biological activities of A-500359 A, C., D. G. J. Antibiot. (Tokyo) 56, 253–258 (2003)." href="/articles/s41467-019-10957-9#ref-CR9" id="ref-link-section-d35905315e1577">9</a></sup>. In the previously published tunicamycin-MraY<sub>CB</sub> complex structure<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 13" title="Hakulinen, J. K. et al. MraY-antibiotic complex reveals details of tunicamycin mode of action. Nat. Chem. Biol. 13, 265–267 (2017)." href="/articles/s41467-019-10957-9#ref-CR13" id="ref-link-section-d35905315e1584">13</a></sup>, the acyl tail of tunicamycin was disordered and therefore was unmodeled (Supplementary Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM1">4d</a>). Our structure of carbacaprazamycin in complex with MraY<sub>AA</sub> definitively demonstrates that the acyl moiety binds to the hydrophobic groove of MraY (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-019-10957-9#Fig2">2c</a>, Supplementary Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM1">6a</a>). SAR studies of carbacaprazamycin indicate that its aliphatic tail is critical for activity; the deacylated caprazol core on its own has no antibacterial activity<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 31" title="Hirano, S., Ichikawa, S. & Matsuda, A. Structure-activity relationship of truncated analogs of caprazamycins as potential anti-tuberculosis agents. Bioorg. Med. Chem. 16, 5123–5133 (2008)." href="/articles/s41467-019-10957-9#ref-CR31" id="ref-link-section-d35905315e1599">31</a></sup>. The core nucleoside geometry of carbacaprazamycin provides the directionality needed to target the hydrophobic binding site with specificity. This observation is consistent with previous work showing the geometry of the lipid carrier substrate, which is thought to bind to the hydrophobic groove, is critical for MraY activity<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 14" title="Yoo, J. et al. GlcNAc-1-P-transferase-tunicamycin complex structure reveals basis for inhibition of N-glycosylation. Nat. Struct. Mol. Biol. 25, 217–224 (2018)." href="/articles/s41467-019-10957-9#ref-CR14" id="ref-link-section-d35905315e1604">14</a></sup>.</p><h3 class="c-article__sub-heading" id="Sec5">The capuramycin binding site</h3><p>Capuramycin consists of uracil and 3-<i>O</i>-methyl ribosyl moieties (collectively referred to as uridine), a 3,4-dihydroxy-3,4-dihyro-2<i>H</i>-pyran moiety, and a caprolactam moiety (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-019-10957-9#Fig1">1b</a>). These moieties bind to the uridine, uridine-adjacent, and caprolactam binding sites (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-019-10957-9#Fig3">3a</a>). The uridine moiety of capuramycin binds to MraY<sub>AA</sub> by engaging in interactions with G194, L195, D196, and F262, as does this moiety in carbacaprazamycin, muraymycin D2, and tunicamycin (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-019-10957-9#Fig3">3b</a>). At the uridine-adjacent site, the 3,4-dihydroxy-3,4-dihyro-2<i>H</i>-pyran moiety of capuramycin, as well as the amide linker to the caprolactam group, forms hydrogen bonds with T75, D193, and the backbone of G264 (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-019-10957-9#Fig3">3b</a>).</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-3" data-title="Fig. 3"><figure><figcaption><b id="Fig3" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 3</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/s41467-019-10957-9/figures/3" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41467-019-10957-9/MediaObjects/41467_2019_10957_Fig3_HTML.png?as=webp"><img aria-describedby="Fig3" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41467-019-10957-9/MediaObjects/41467_2019_10957_Fig3_HTML.png" alt="figure 3" loading="lazy" width="685" height="395"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-3-desc"><p>Capuramycin forms a unique interaction with the caprolactam site on MraY<sub>AA</sub>. <b>a</b> The binding pockets occupied by capuramycin (yellow) on the cytoplasmic face of MraY<sub>AA</sub> include the uridine (red), uridine-adjacent (lime green), and caprolactam (pink) sites. <b>b</b> A zoomed-in view of the capuramycin binding site in the same orientation as shown in <b>a</b>. Residues forming interactions with capuramycin are labeled and color-coded according to the binding pocket to which they belong. Hydrogen bonds are represented by dashed lines. <b>c</b> A view of the capuramycin binding site rotated 60° relative to the orientation in <b>a</b> to highlight the caprolactam binding site. The surface of MraY<sub>AA</sub> is shown in transparent gray with residues forming the shallow caprolactam binding pocket (pink dashes lines) labeled. TMs (numbers) and Loops (letters) are labeled throughout. The side chains of residues K70 and K121 are disordered in the MraY<sub>AA</sub>-capuramycin complex structure</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/s41467-019-10957-9/figures/3" data-track-dest="link:Figure3 Full size image" aria-label="Full size image figure 3" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>Notably, the caprolactam moiety of capuramycin assumes a unique binding site on the cytoplasmic face of MraY that has not been previously observed in muraymycin D2 and tunicamycin, and is unique among all MraY nucleoside inhibitors. The caprolactam occupies a very shallow, mostly hydrophobic pocket (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-019-10957-9#Fig3">3c</a>). Extensive SAR studies have been carried out on the caprolactam moiety of capuramycin. Replacing the caprolactam moiety with a small functional group, such as a hydroxyl, amide, or methoxy group, results in dramatic loss of inhibitory activity<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 32" title="Muramatsu, Y. et al. Studies on novel bacterial translocase I inhibitors, A-500359s. III. Deaminocaprolactam derivatives of capuramycin: A-500359 E, F, H; M-1 and M-2. J. Antibiot. (Tokyo) 56, 259–267 (2003)." href="/articles/s41467-019-10957-9#ref-CR32" id="ref-link-section-d35905315e1688">32</a></sup>. In addition, modifying capuramycin with alkyl groups of various lengths in place of the caprolactam group reduces inhibition. However, capuramycin derivatives with cyclic functional groups instead of the caprolactam, such as phenyl, phenethyl, benzyl, cyclohexyl, and cycloheptyl moieties, have comparable activity to capuramycin itself<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 22" title="Hotoda, H. et al. Synthesis and antimycobacterial activity of capuramycin analogues. Part 1: substitution of the azepan-2-one moiety of capuramycin. Bioorg. Med. Chem. Lett. 13, 2829–2832 (2003)." href="/articles/s41467-019-10957-9#ref-CR22" id="ref-link-section-d35905315e1692">22</a></sup>. These findings are consistent with the structure of the caprolactam binding pocket, which is a superficial groove (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-019-10957-9#Fig3">3c</a>); shape complementarity likely enhances affinity to the caprolactam pocket. Although part of caprolactam binding site and some nearby residues are conserved, neighboring sites are variable among MraY orthologs (Supplementary Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM1">6b</a>). Taking into account MraY sequence variability in the regions neighboring the caprolactam binding pocket could lead to the development of capuramycin analogs with more narrow-spectrum activity.</p><h3 class="c-article__sub-heading" id="Sec6">The 3′-hydroxymureidomycin A binding site</h3><p>The mureidomycins contain a tetrapeptide, which includes a <i>meta</i>-tyrosine moiety and an urea dipeptide motif (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-019-10957-9#Fig1">1c</a>). The tetrapeptide connects to the uridine moiety via an enamide linker. The synthetic derivative 3′-hydroxymureidomycin A, which differs from the mureidomycins in that it contains two hydroxyl groups on the ribosyl moiety instead of one, was designed and synthesized based on a previous study<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Okamoto, K. et al. Total synthesis and biological evaluation of pacidamycin D and its 3′-hydroxy analogue. J. Org. Chem. 77, 1367–1377 (2012)." href="/articles/s41467-019-10957-9#ref-CR33" id="ref-link-section-d35905315e1716">33</a></sup> (<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM1">Supplementary Methods</a>). The substructures of 3′-hydroxymureidomycin A bind to the uridine, uridine-adjacent, and TM9b/Loop E pockets on the cytoplasmic side of MraY (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-019-10957-9#Fig4">4a</a>). The uridine moiety of 3′-hydroxymureidomycin A binds in a similar manner as observed for other nucleoside inhibitors, with added stabilization from a hydrogen bond with D193 (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-019-10957-9#Fig4">4b</a>). The uridine-adjacent pocket binds the <i>meta</i>-tyrosine moiety of 3′-hydroxymureidomycin A wherein T75 forms a hydrogen bond with the hydroxyl group of <i>meta</i>-tyrosine and N190 anchors the terminal amino group. This same amino group in the <i>meta</i>-tyrosine interacts with D265, the conserved and essential aspartate residue responsible for coordinating the Mg<sup>2+</sup> cofactor in MraY<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Chung, B. C. et al. Crystal structure of MraY, an essential membrane enzyme for bacterial cell wall synthesis. Science 341, 1012–1016 (2013)." href="/articles/s41467-019-10957-9#ref-CR17" id="ref-link-section-d35905315e1741">17</a></sup>.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-4" data-title="Fig. 4"><figure><figcaption><b id="Fig4" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 4</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/s41467-019-10957-9/figures/4" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41467-019-10957-9/MediaObjects/41467_2019_10957_Fig4_HTML.png?as=webp"><img aria-describedby="Fig4" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41467-019-10957-9/MediaObjects/41467_2019_10957_Fig4_HTML.png" alt="figure 4" loading="lazy" width="685" height="335"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-4-desc"><p>A detailed view of the interactions between MraY<sub>AA</sub> and 3′-hydroxymureidomycin A. <b>a</b> The binding pockets recognized by 3′-hydroxymureidomycin A (bright green) on the cytoplasmic side of MraY<sub>AA</sub> include the uridine (red), uridine-adjacent (lime green), TM9b/Loop E (purple), and Mg<sup>2+</sup> (gold) sites. <b>b</b> A zoomed-in view of the 3′-hydroxymureidomycin A binding site in the same orientation as shown in <b>a</b>. Residues forming interactions with 3′-hydroxymureidomycin A are labeled and color-coded according the binding pocket to which they belong. Hydrogen bonds are represented by dashed lines. <b>c</b> A view of the 3′-hydroxymureidomycin A binding site rotated 45° relative to the orientation shown in <b>a</b>. TMs (numbers) and Loops (letters) are labeled throughout. The side chain of residue K70 is disordered in the MraY<sub>AA</sub>-3′-hydroxymureidomycin A complex structure</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/s41467-019-10957-9/figures/4" data-track-dest="link:Figure4 Full size image" aria-label="Full size image figure 4" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>The TM9b/Loop E pocket is extensively occupied by 3′-hydroxymureidomycin A (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-019-10957-9#Fig4">4c</a>). The urea dipeptide motif in 3′-hydroxymureidomycin A interacts with the TM9b/Loop E pocket by engaging Q305, A321, and H325. Muraymycin D2 also includes a urea dipeptide motif, although the identities of the amino acids in each inhibitor differ; 3′-hydroxymureidomycin A contains methionine-urea-<i>meta</i>-tyrosine, while the analogous substructure in muraymycin D2 is l-<i>epi</i>-capreomycidine-urea-valine (Supplementary Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM1">4a</a>). Interestingly, despite the different amino acids in each compound, the urea dipeptide motif of each inhibitor binds to the TM9b/LoopE pocket similarly (Supplementary Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM1">6c</a>).</p><h3 class="c-article__sub-heading" id="Sec7">The uridine site is common to MraY nucleoside inhibitors</h3><p>A feature common to all MraY-inhibitor complex structures is the binding pocket that accommodates the uridine present in each nucleoside inhibitor. Structural superimposition of all five inhibitor-bound MraY crystal structures reveals that the uracil and ribosyl moieties of each nucleoside inhibitor overlap (Supplementary Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM1">7</a>). The residues that form the uracil binding pocket of MraY (K70, G194, L195, D196, and F262) are likely involved in binding the natural substrate of this enzyme, UM5A, which also contains a uracil. There is some spatial tolerance within the uridine pocket of MraY for positioning of the uracil moiety. For example, the capuramycin and 3′-hydroxymureidomycin A uracil moieties deviate from that of the other nucleoside inhibitors (Supplementary Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM1">7</a>). Although the uridine pocket is the most defined and enclosed pocket on the cytoplasmic surface of MraY, it is relatively accommodating to a variety of ligands containing a uracil moiety.</p><p>The ribosyl moiety of each inhibitor (or the 3′-O-methylated ribosyl, as in the case of capuramycin) also assumes a very similar orientation in each structure (Supplementary Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM1">7</a>). No hydrogen-bonding interactions are observed between MraY and the hydroxyl groups of the ribosyl moiety in each inhibitor, which are mostly exposed to the cytoplasm. It appears that the geometry assumed by the ribosyl moiety may provide the directionality needed for each inhibitor to occupy key binding sites on the cytoplasmic face of MraY.</p><h3 class="c-article__sub-heading" id="Sec8">Diverse pharmacophores target the uridine-adjacent pocket</h3><p>The uridine-adjacent pocket is lined by amino acid residues T75, N190, D193, and G264. Interestingly, the spatial orientation of these residues is similar in each inhibitor-bound structure, but the pocket can accommodate very different chemical moieties (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-019-10957-9#Fig5">5</a>). Carbacaprazamycin and muraymycin D2 each contain a 5-aminoribosyl moiety, which occupies the uridine-adjacent pocket (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-019-10957-9#Fig5">5a–b</a>). The amino group of the 5-aminoribosyl moiety in carbacaprazamycin and in muraymycin D2 forms a critical interaction with D193 in the uridine-adjacent pocket. SAR studies on the 5-aminoribose-nucleoside core shared by muraymycin and carbacaprazamycin demonstrate that replacing the amino group in the 5-aminoribosyl moiety dramatically reduces inhibitory activity<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 34" title="Dini, C. et al. Synthesis of analogues of the O-beta-D-ribofuranosyl nucleoside moiety of liposidomycins. Part 1: contribution of the amino group and the uracil moiety upon the inhibition of MraY. Bioorg. Med. Chem. Lett. 11, 529–531 (2001)." href="/articles/s41467-019-10957-9#ref-CR34" id="ref-link-section-d35905315e1841">34</a></sup>. Furthermore, mutagenesis studies on MraY<sub>AA</sub> show that a D193N mutation nearly completely abolishes its affinity to muraymycin D2<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="Chung, B. C. et al. Structural insights into inhibition of lipid I production in bacterial cell wall synthesis. Nature 533, 557–560 (2016)." href="/articles/s41467-019-10957-9#ref-CR18" id="ref-link-section-d35905315e1847">18</a></sup>.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-5" data-title="Fig. 5"><figure><figcaption><b id="Fig5" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 5</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/s41467-019-10957-9/figures/5" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41467-019-10957-9/MediaObjects/41467_2019_10957_Fig5_HTML.png?as=webp"><img aria-describedby="Fig5" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41467-019-10957-9/MediaObjects/41467_2019_10957_Fig5_HTML.png" alt="figure 5" loading="lazy" width="685" height="378"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-5-desc"><p>Structurally diverse moieties occupy the uridine-adjacent binding pocket in MraY<sub>AA</sub>. <b>a</b> Carbacaprazamycin (magenta), <b>b</b> muraymycin D2 (orange), <b>c</b> capuramycin (yellow), <b>d</b> 3′-hydroxymureidomycin A (green), <b>e</b> tunicamycin (slate) binding interactions at the uridine-adjacent pocket. Residues labeled in black and blue form side chain and backbone interactions with the inhibitor, respectively. Hydrogen bonds are represented by black dashed lines. Residue numbering is shown for MraY<sub>AA</sub> except in <b>e</b>, which shows residue numbering for MraY<sub>CB</sub> with the corresponding residues in MraY<sub>AA</sub> provided in parentheses</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/s41467-019-10957-9/figures/5" data-track-dest="link:Figure5 Full size image" aria-label="Full size image figure 5" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>Capuramycin binds the uridine-adjacent pocket with a 3,4-dihydroxy-3,4-dihyro-2<i>H</i>-pyran moiety (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-019-10957-9#Fig5">5c</a>). One hydroxyl group of the 3,4-dihydroxy-3,4-dihyro-2<i>H</i>-pyran moiety engages in a hydrogen-bonding interaction with D193 and the backbone amino group of G264. Replacing this hydroxyl group with a hydrogen leads to an order of magnitude decrease in capuramycin inhibitory activity<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 9" title="Muramatsu, Y., Ishii, M. M. & Inukai, M. Studies on novel bacterial translocase I inhibitors, A-500359s. II. Biological activities of A-500359 A, C., D. G. J. Antibiot. (Tokyo) 56, 253–258 (2003)." href="/articles/s41467-019-10957-9#ref-CR9" id="ref-link-section-d35905315e1909">9</a></sup>. In the 3′-hydroxymureidomycin A-bound structure of MraY, the <i>meta</i>-tyrosine moiety engages in interactions with N190 and T75 in the uridine-adjacent pocket (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-019-10957-9#Fig5">5d</a>). The mureidomycin class of MraY nucleoside inhibitors belongs to a larger group of structurally-similar uridylpeptide compounds, including the pacidamycins and napsamycins, which differ with respect to the types of amino acid residues found in the peptidic moiety of each inhibitor<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 6" title="Winn, M., Goss, R. J., Kimura, K. & Bugg, T. D. Antimicrobial nucleoside antibiotics targeting cell wall assembly: recent advances in structure-function studies and nucleoside biosynthesis. Nat. Prod. Rep. 27, 279–304 (2010)." href="/articles/s41467-019-10957-9#ref-CR6" id="ref-link-section-d35905315e1920">6</a></sup>. In place of the <i>meta</i>-tyrosine moiety found in the mureidomycins, the napsamycins have an unusual bicyclic amino acid residue, which contains <i>meta</i>-tyrosine, and some analogs of pacidamycin contain an alanine residue at the analogous position. Mureidomycin, pacidamycin, and napsamycins exhibit similar activity<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 35" title="Isono, F. et al. Mureidomycins E and F, minor components of mureidomycins. J. Antibiot. (Tokyo) 46, 1203–1207 (1993)." href="/articles/s41467-019-10957-9#ref-CR35" id="ref-link-section-d35905315e1930">35</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 36" title="Chatterjee, S. et al. Napsamycins, new Pseudomonas active antibiotics of the mureidomycin family from Streptomyces sp. HIL Y-82,11372. J. Antibiot. (Tokyo) 47, 595–598 (1994)." href="/articles/s41467-019-10957-9#ref-CR36" id="ref-link-section-d35905315e1933">36</a></sup> and it is likely that the uridine-adjacent site accommodates the various amino acid residues found in each uridylpeptide subclass.</p><p>Compared to the extensive hydrogen-bonding networks formed by carbacaprazamycin, muraymycin D2, capuramycin, and 3′-hydroxymureidomycin A in the uridine-adjacent pocket, tunicamycin makes relatively few interactions at that site (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-019-10957-9#Fig5">5e</a>). Instead, the tunicamine sugar moiety of tunicamycin picks up hydrogen bonds with additional residues near the uridine-adjacent pocket, including K133 (K111 in MraY<sub>CB</sub>), and a backbone interaction with L191 (F173 in MraY<sub>CB</sub>) (Supplementary Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM1">4d</a>). These interactions are unique to tunicamycin. Tunicamycin is the only non-selective nucleoside inhibitor among the five known classes, with off-target effects on the human MraY paralog, GPT. GPT lacks a binding pocket analogous to the uridine-adjacent pocket in MraY<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 14" title="Yoo, J. et al. GlcNAc-1-P-transferase-tunicamycin complex structure reveals basis for inhibition of N-glycosylation. Nat. Struct. Mol. Biol. 25, 217–224 (2018)." href="/articles/s41467-019-10957-9#ref-CR14" id="ref-link-section-d35905315e1950">14</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 15" title="Dong, Y. Y. et al. Structures of DPAGT1 explain glycosylation disease mechanisms and advance TB antibiotic design. Cell 175, 1045–1058 (2018). e1016." href="/articles/s41467-019-10957-9#ref-CR15" id="ref-link-section-d35905315e1953">15</a></sup>. Therefore, targeting the uridine-adjacent pocket could be a strategy to engineer selectivity of nucleoside inhibitors for MraY over GPT. Occupying the uridine-adjacent pocket is not required for MraY inhibition, but it enhances inhibitory potency. This observation is bolstered by SAR studies demonstrating that muraymycin analogs lacking the 5-aminoribosyl moiety that binds the uridine-adjacent site, such as muraymycins A5 and C4 and some synthetic 5′-defuntionalized muraymycin derivatives, retain inhibitory activity<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="McDonald, L. A. et al. Structures of the muraymycins, novel peptidoglycan biosynthesis inhibitors. J. Am. Chem. Soc. 124, 10260–10261 (2002)." href="#ref-CR37" id="ref-link-section-d35905315e1958">37</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Spork, A. P. et al. Lead structures for new antibacterials: stereocontrolled synthesis of a bioactive muraymycin analogue. Chemistry 20, 15292–15297 (2014)." href="#ref-CR38" id="ref-link-section-d35905315e1958_1">38</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 39" title="Spork, A. P., Koppermann, S., Schier Nee Wohnig, S., Linder, R. & Ducho, C. Analogues of muraymycin nucleoside antibiotics with epimeric uridine-derived core structures. Molecules 23, 2868–2888 (2018)." href="/articles/s41467-019-10957-9#ref-CR39" id="ref-link-section-d35905315e1961">39</a></sup>. The uridine-adjacent pocket is an opportunistic site that is highly tolerant to a wide variety of pharmacophores and can greatly enhance inhibitor binding to and specificity for MraY.</p><h3 class="c-article__sub-heading" id="Sec9">Each MraY inhibitor binds TM9b/Loop E except capuramycin</h3><p>There is variability in the degree to which each inhibitor interacts with the most structurally plastic regions of MraY, including TM9b, Loop E, and the Loop E helix. The inhibitors 3′-hydroxymureidomycin A and muraymycin D2 make the most extensive interactions at this site, forming hydrogen bonds with Q305 and A321 in TM9b via the carboxylate and urea moieties these compounds share (Supplementary Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM1">6c</a>). In addition, 3′-hydroxymureidomycin A and muraymycin D2 form an interaction with H325 in the Loop E helix, which is also observed in carbacaprazamycin and tunicamycin binding (Supplementary Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM1">8</a>). Muraymycin D2 interacts with H325 via a water-mediated hydrogen-bonding network, which also includes H324, and the L-<i>epi</i>-capreomycidine moiety of the inhibitor packs against H325 as well. Carbacaprazamycin, tunicamycin, and 3′-hydroxymureidomycin A engage in hydrogen bonds with H325 directly (Supplementary Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM1">8</a>).</p><p>Capuramycin is unique among the five classes of nucleoside MraY inhibitors because it binds away from TM9b and the Loop E helix (Supplementary Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM1">8e</a>). Consistent with this observation, Loop E in the capuramycin-bound structure is disordered, likely because inhibitor binding does not stabilize the loop. Unlike the other MraY natural product inhibitors, capuramycin is too far away from the Loop E helix to interact with H325.</p><h3 class="c-article__sub-heading" id="Sec10">Two nucleoside inhibitors bind the Mg<sup>2+</sup> site</h3><p>Three aspartate residues (D117, D118, D265 in MraY<sub>AA</sub>, termed the DDD motif) are critical for MraY enzymatic activity and have been thought to play a critical role in catalysis<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Chung, B. C. et al. Crystal structure of MraY, an essential membrane enzyme for bacterial cell wall synthesis. Science 341, 1012–1016 (2013)." href="/articles/s41467-019-10957-9#ref-CR17" id="ref-link-section-d35905315e2004">17</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 40" title="Al-Dabbagh, B. et al. Active site mapping of MraY, a member of the polyprenyl-phosphate N-acetylhexosamine 1-phosphate transferase superfamily, catalyzing the first membrane step of peptidoglycan biosynthesis. Biochemistry 47, 8919–8928 (2008)." href="/articles/s41467-019-10957-9#ref-CR40" id="ref-link-section-d35905315e2007">40</a></sup>. The structure of MraY<sub>AA</sub> in complex with its Mg<sup>2+</sup> cofactor reveals that D265 is the Mg<sup>2+</sup>-coordinating residue<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Chung, B. C. et al. Crystal structure of MraY, an essential membrane enzyme for bacterial cell wall synthesis. Science 341, 1012–1016 (2013)." href="/articles/s41467-019-10957-9#ref-CR17" id="ref-link-section-d35905315e2018">17</a></sup>. Among the five MraY nucleoside inhibitors, only 3′-hydroxymureidomycin A and tunicamycin interact with D265 (Supplementary Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM1">9</a>). This interaction is formed by the tunicamine sugar moiety in tunicamycin and the amino group of the <i>meta</i>-tyrosine in 3′-hydroxymureidomycin A. Our structural observations are fully consistent with previous studies demonstrating that tunicamycin and mureidomycin compete with the Mg<sup>2+</sup> cofactor binding to MraY. For example, increasing MgCl<sub>2</sub> concentration decreases the equilibrium binding constant (K<sub>d</sub>) of tunicamycin to MraY<sub>AA</sub>, as measured by isothermal titration calorimetry<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 14" title="Yoo, J. et al. GlcNAc-1-P-transferase-tunicamycin complex structure reveals basis for inhibition of N-glycosylation. Nat. Struct. Mol. Biol. 25, 217–224 (2018)." href="/articles/s41467-019-10957-9#ref-CR14" id="ref-link-section-d35905315e2037">14</a></sup>. An analogous enzymatic assay performed with MraY from <i>E. coli</i> (MraY<sub>EC</sub>) demonstrates that the inhibitory activity of mureidomycin and analogs thereof decreases with increasing concentrations of MgCl<sub>2</sub><sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 41" title="Howard, N. I. & Bugg, T. D. H. Synthesis and activity of 5′-Uridinyl dipeptide analogues mimicking the amino terminal peptide chain of nucleoside antibiotic mureidomycin A. Bioorg. Med. Chem. 11, 3083–3099 (2003)." href="/articles/s41467-019-10957-9#ref-CR41" id="ref-link-section-d35905315e2047">41</a></sup>. The authors of this study proposed that the amide linkage of the meta-tyrosine moiety in mureidomycin could interact with the Mg<sup>2+</sup> cofactor binding site<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 41" title="Howard, N. I. & Bugg, T. D. H. Synthesis and activity of 5′-Uridinyl dipeptide analogues mimicking the amino terminal peptide chain of nucleoside antibiotic mureidomycin A. Bioorg. Med. Chem. 11, 3083–3099 (2003)." href="/articles/s41467-019-10957-9#ref-CR41" id="ref-link-section-d35905315e2054">41</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 42" title="A Gentle, C., A. Harrison, S., Inukai, M. & D. H. Bugg, T. Structure–function studies on nucleoside antibiotic mureidomycin A: synthesis of 5′-functionalised uridine models. J. Chem. Soc. Perkin Trans. 1, 1287–1294 (1999)." href="/articles/s41467-019-10957-9#ref-CR42" id="ref-link-section-d35905315e2057">42</a></sup>, as in fact our structure of MraY<sub>AA</sub> bound to 3′-hydroxymureidomycin A demonstrates (Supplementary Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM1">9</a>). None of the five MraY nucleoside inhibitors for which X-ray crystal structures are available form interactions with the remaining two conserved aspartate residues of the DDD motif (D117 and D118 in MraY<sub>AA</sub>) (Supplementary Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM1">9</a>).</p><h3 class="c-article__sub-heading" id="Sec11">The hot spots of inhibition on MraY are summarized by a “barcode”</h3><p>Occupying the uridine binding pocket appears to be critical for the inhibition of MraY by nucleoside natural products, which all bind to this pocket in a similar manner (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-019-10957-9#Fig6">6a</a>). However, each nucleoside inhibitor forms different interactions with the other binding sites on the cytoplasmic face of MraY (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-019-10957-9#Fig6">6a</a>). These sites constitute the druggable hot spots (HSs) of MraY inhibition, which we name HS1–6, representing the uridine-adjacent, TM9b/Loop E, caprolactam, hydrophobic, Mg<sup>2+</sup> cofactor, and tunicamycin binding pockets, respectively (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-019-10957-9#Fig6">6b</a>). An analysis of interactions each inhibitor forms with the residues comprising the six HSs reveals trends among nucleoside inhibitors that provide mechanistic insight into MraY inhibition, which we have summarized for each compound with a “barcode” tool (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-019-10957-9#Fig6">6c</a>). This analysis reveals that in addition to binding the uridine pocket, each inhibitor must form substantial interactions with at least two HSs. For example, capuramycin binds HS1 and HS3, while carbacaprazamycin occupies HS1 and HS4, and forms one hydrogen bond in HS2 (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-019-10957-9#Fig6">6c</a>). Both 3′-hydroxymureidomycin A and muraymycin D2 form interactions with HS1 and HS2; however, 3′-hydroxymureidomycin A makes two fewer contacts at these sites than does muraymycin D2 and instead picks up an additional interaction in HS5. Tunicamycin has a substantially different HS binding profile than other nucleoside inhibitors (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-019-10957-9#Fig6">6c</a>). Tunicamycin makes few interactions in HS1 and HS2, likely interacts with HS4, binds HS5, and also forms hydrogen bonds in HS6, a site on MraY not exploited by other nucleoside inhibitors. Tunicamycin achieves these interactions via its tunicamine sugar and GlcNAc moieties, two pharmacophores that are recognized by eukaryotic GPT<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 14" title="Yoo, J. et al. GlcNAc-1-P-transferase-tunicamycin complex structure reveals basis for inhibition of N-glycosylation. Nat. Struct. Mol. Biol. 25, 217–224 (2018)." href="/articles/s41467-019-10957-9#ref-CR14" id="ref-link-section-d35905315e2100">14</a></sup>. The binding signature of tunicamycin among the nucleoside natural products is consistent with its promiscuous inhibitory activity.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-6" data-title="Fig. 6"><figure><figcaption><b id="Fig6" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 6</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/s41467-019-10957-9/figures/6" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41467-019-10957-9/MediaObjects/41467_2019_10957_Fig6_HTML.png?as=webp"><img aria-describedby="Fig6" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41467-019-10957-9/MediaObjects/41467_2019_10957_Fig6_HTML.png" alt="figure 6" loading="lazy" width="685" height="1230"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-6-desc"><p>Summary of the hot spots of MraY inhibition. <b>a</b> Structural overlay of MraY<sub>AA</sub> bound to carbacaprazamycin (magenta), capuramycin (yellow), 3′-hydroxymureidomycin A (green), and muraymycin D2 (orange), and MraY<sub>CB</sub> bound to tunicamycin (slate) viewed from the cytoplasm. <b>b</b> Structure of MraY<sub>AA</sub> in surface representation with inhibitor binding site hot spots (HSs) color-coded and labeled as follows: uridine (red), uridine-adjacent (HS1; lime green), TM9b/LoopE (HS2; purple), caprolactam (HS3; pink), hydrophobic (HS4; cyan), Mg<sup>2+</sup> (HS5; gold), and tunicamycin (HS6; brown). <b>c</b> A barcode representing the interactions each nucleoside inhibitor makes with HS1–6. The residues shown underneath each HS label are found at that site in MraY. Amino acid residue numbering is shown for MraY<sub>AA</sub> and color-coding is consistent with <b>b</b>. Each row represents a different compound: carbacaprazamycin (CAR), capuramycin (CAP), 3′-hydroxymureidomycin A (MUR), muraymycin D2 (MD2), and tunicamycin (TUN). A dark gray square represents an interaction between the corresponding inhibitor and residue. A white square indicates that no contact is made. Squares colored light gray represent that either the amino acid residue side chain or the inhibitor substructure is not resolved in the crystal structure, but likely makes the relevant binding interaction. The side chains of residues K70 and K121 are disordered in the MraY<sub>AA</sub>-capuramycin complex structure. The side chain of residue K70 is disordered in the MraY<sub>AA</sub>-3′-hydroxymureidomycin A complex structure</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/s41467-019-10957-9/figures/6" data-track-dest="link:Figure6 Full size image" aria-label="Full size image figure 6" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div></div></div></section><section data-title="Discussion"><div class="c-article-section" id="Sec12-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec12">Discussion</h2><div class="c-article-section__content" id="Sec12-content"><p>Our structures of MraY bound to naturally occurring nucleoside inhibitors provide insights into the druggability of the shallow, solvent-exposed binding site on the cytoplasmic surface of MraY. Surface binding sites have traditionally been challenging to target for drug-development<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 43" title="Arkin, M. R., Tang, Y. & Wells, J. A. Small-molecule inhibitors of protein-protein interactions: progressing toward the reality. Chem. Biol. 21, 1102–1114 (2014)." href="/articles/s41467-019-10957-9#ref-CR43" id="ref-link-section-d35905315e2158">43</a></sup>. Our comparative structural analyses elucidate the design principle of MraY natural product inhibitors, serving as an instructive example in which nature overcomes the challenge of targeting surface binding sites.</p><p>The only defined “pocket” on the cytoplasmic face of MraY binds the uracil moiety of each nucleoside inhibitor. However, uridine itself cannot be a strong MraY inhibitor, if at all; therefore, MraY inhibition can be achieved by also targeting hot spots on the cytosolic surface near the uridine binding site. Our structural studies, in conjunction with previous SAR data, reveal the importance of each druggable hot spot in MraY, and how these sites can be exploited in multiple combinations to maximize the therapeutic potential of MraY-targeted inhibitors.</p><p>The uridine-adjacent pocket, HS1, is perhaps the most druggable site on MraY, as this pocket can recognize a surprisingly wide variety of pharmacophores, including 5-aminoribosyl, <i>meta</i>-tyrosine, and 3,4-dihydroxy-3,4-dihyro-2<i>H</i>-pyran moieties. Because tunicamycin does not extensively utilize this site, targeting it likely improves selectivity for MraY, thereby lessening off-target effects on human GPT that lead to cytotoxicity. Important pharmacophore requirements for HS1 include shape complementarity, the presence of hydrogen bond donor and acceptor functional groups, and perhaps most critically, spatial positioning relative to the uridine moiety. The binding of muraymycin D2 to MraY has been described as akin to a plug inserting into an electrical socket, with the uracil and 5-aminoribosyl moieties serving as the two prongs of the plug<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="Chung, B. C. et al. Structural insights into inhibition of lipid I production in bacterial cell wall synthesis. Nature 533, 557–560 (2016)." href="/articles/s41467-019-10957-9#ref-CR18" id="ref-link-section-d35905315e2174">18</a></sup>. Our structures reveal that the 5-aminoribosyl prong, which binds HS1, can be replaced by a variety of chemical moieties, provided that the geometry of the inhibitor core structure allows for a “plug-like” two-pronged shape that binds both HS1 and the uracil pocket. In muraymycin D2, carbacaprazamycin, and capuramycin, this two-pronged geometry is formed in part by the stereocenter at the 5′ position of the nucleoside ribosyl group (Supplementary Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM1">7</a>). The important role of this chiral center is underscored by two SAR studies of epimeric nucleoside MraY inhibitors. The core structure of muraymycin D2, 5-aminoribosyl uridine, inhibits MraY with 100-fold greater potency if the stereocenter at the 5′ position of the nucleoside ribosyl group is <i>S</i>- rather than <i>R</i>-configuration<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 44" title="Dini, C. et al. Synthesis of the nucleoside moiety of liposidomycins: elucidation of the pharmacophore of this family of MraY inhibitors. Bioorg. Med. Chem. Lett. 10, 1839–1843 (2000)." href="/articles/s41467-019-10957-9#ref-CR44" id="ref-link-section-d35905315e2188">44</a></sup>. However, a recent study demonstrates that muraymycin analogs lacking the 5-aminoribosyl moiety tolerate either <i>S</i>- or <i>R</i>-configuration at the 5′ position of the ribosyl group<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 39" title="Spork, A. P., Koppermann, S., Schier Nee Wohnig, S., Linder, R. & Ducho, C. Analogues of muraymycin nucleoside antibiotics with epimeric uridine-derived core structures. Molecules 23, 2868–2888 (2018)." href="/articles/s41467-019-10957-9#ref-CR39" id="ref-link-section-d35905315e2198">39</a></sup>. Collectively, these data are consistent with the notion that the geometry of the nucleoside ribosyl moiety is conducive to forming the two-pronged molecular shape that can bind to the uracil and HS1 pockets on MraY. Interestingly, the stereocenter at the 5′ position of the ribosyl group is only one mechanism by which nature has developed two-pronged inhibitors of MraY. The 5′ position of the ribosyl group in 3′-hydroxymureidomycin A is not a chiral center; there is instead a 4′, 5′-enamide linker at this site. However, the second prong of 3′-hydroxymureidomycin A (<i>meta</i>-tyrosine) still accesses HS1 due to the stereochemistry of its core peptidic structure.</p><p>HS2, the TM9b/Loop E pocket, can be accessed via interaction with H325 in the Loop E helix, as each nucleoside inhibitor except capuramycin demonstrates. Functionalizing the carboxamide in capuramycin, such as introducing a linker or larger moiety, may improve the affinity of this class of compounds by extending the capuramycin binding site to HS2. More extensive interactions with HS2 are observed in 3′-hydroxymureidomycin A and muraymycin D2 binding, which is primarily achieved via a urea motif found in each compound. These two structures demonstrate that several chemical moieties are tolerated at the amino acid sites in the urea dipeptide motif.</p><p>HS3, which binds caprolactam, is a cryptic site uniquely occupied by capuramycin. Due to the sequence variability at and near this site (Supplementary Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM1">6b</a>), this moiety may be functionalized for the design of narrow-spectrum antibiotics. Extensive studies have been conducted to understand and improve upon the inherent antimycobacterial activity of the capuramycins<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 9" title="Muramatsu, Y., Ishii, M. M. & Inukai, M. Studies on novel bacterial translocase I inhibitors, A-500359s. II. Biological activities of A-500359 A, C., D. G. J. Antibiot. (Tokyo) 56, 253–258 (2003)." href="/articles/s41467-019-10957-9#ref-CR9" id="ref-link-section-d35905315e2215">9</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 24" title="Reddy, V. M., Einck, L. & Nacy, C. A. In vitro antimycobacterial activities of capuramycin analogues. Antimicrob. Agents Chemother. 52, 719–721 (2008)." href="/articles/s41467-019-10957-9#ref-CR24" id="ref-link-section-d35905315e2218">24</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Nikonenko, B. V. et al. Activity of SQ641, a capuramycin analog, in a murine model of tuberculosis. Antimicrob. Agents Chemother. 53, 3138–3139 (2009)." href="#ref-CR45" id="ref-link-section-d35905315e2221">45</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Nikonenko, B. et al. Therapeutic efficacy of SQ641-NE against Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 58, 587–589 (2014)." href="#ref-CR46" id="ref-link-section-d35905315e2221_1">46</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 47" title="Siricilla, S., Mitachi, K., Wan, B., Franzblau, S. G. & Kurosu, M. Discovery of a capuramycin analog that kills nonreplicating Mycobacterium tuberculosis and its synergistic effects with translocase I inhibitors. J. Antibiot. (Tokyo) 68, 271–278 (2015)." href="/articles/s41467-019-10957-9#ref-CR47" id="ref-link-section-d35905315e2224">47</a></sup>. Among the various capuramycin analogs produced, perhaps the most promising is SQ641, which kills <i>Mycobacterium tuberculosis</i> faster than some existing antitubercular drugs<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 24" title="Reddy, V. M., Einck, L. & Nacy, C. A. In vitro antimycobacterial activities of capuramycin analogues. Antimicrob. Agents Chemother. 52, 719–721 (2008)." href="/articles/s41467-019-10957-9#ref-CR24" id="ref-link-section-d35905315e2231">24</a></sup>. Recent studies also show that SQ641 effectively treats <i>Clostridium difficile</i> infection<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 48" title="Moore, J. H. 2nd et al. Treatment of Clostridium difficile infection using SQ641, a capuramycin analogue, increases post-treatment survival and improves clinical measures of disease in a murine model. J. Antimicrob. Chemother. 71, 1300–1306 (2016)." href="/articles/s41467-019-10957-9#ref-CR48" id="ref-link-section-d35905315e2239">48</a></sup>. SQ641 differs from capuramycin in that it contains a 2′-<i>O</i>-acyl group at the ribosyl moiety and the 7-position of the caprolactam moiety is methylated. The caprolactam binding pocket in MraY<sub>AA</sub> is composed of K121, L122, and K125. While K121 is highly conserved among MraY orthologs, L122 and K125 are not. The equivalent residues in the MraY ortholog from <i>M. tuberculosis</i> H37Rv (Rv2156c) are I106 and S109; therefore, introducing a hydrogen bond acceptor on the caprolactam moiety of SQ641 may improve its antitubercular activity. The MraY ortholog from <i>C. difficle</i> contains additional amino acids at this site, which also may be targeted by modifying the caprolactam moiety.</p><p>HS4, the hydrophobic binding site on MraY, can accommodate aliphatic chains with widely varying structures. Several naturally occurring liposidomycins have been identified with structural variance in their aliphatic chains<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Kimura, K. et al. New types of liposidomycins that inhibit bacterial peptidoglycan synthesis and are produced by Streptomyces. I. Producing organism and medium components. J. Antibiot. (Tokyo) 51, 640–646 (1998)." href="#ref-CR49" id="ref-link-section-d35905315e2257">49</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Kimura, K. et al. New types of liposidomycins that inhibit bacterial peptidoglycan synthesis and are produced by Streptomyces. II. Isolation and structure elucidation. J. Antibiot. (Tokyo) 51, 647–654 (1998)." href="#ref-CR50" id="ref-link-section-d35905315e2257_1">50</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 51" title="Esumi, Y. et al. New types of liposidomycins produced by Streptomyces that inhibit bacterial peptidoglycan synthesis. Structure elucidation of fatty acid components by tandem mass spectrometry. J. Antibiot. (Tokyo) 52, 281–287 (1999)." href="/articles/s41467-019-10957-9#ref-CR51" id="ref-link-section-d35905315e2260">51</a></sup>. For example, liposidomycin Types I and III have a branched lipid tail with ester linkage, while Types II and IV contain a single linear chain<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 52" title="Kimura, K. et al. Selective inhibition of the bacterial peptidoglycan biosynthesis by the new types of liposidomycins. J. Antibiot. (Tokyo) 51, 1099–1104 (1998)." href="/articles/s41467-019-10957-9#ref-CR52" id="ref-link-section-d35905315e2264">52</a></sup>. Unsaturation, methylation, and functionalization at various sites on the aliphatic tail moiety are broadly tolerated<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 6" title="Winn, M., Goss, R. J., Kimura, K. & Bugg, T. D. Antimicrobial nucleoside antibiotics targeting cell wall assembly: recent advances in structure-function studies and nucleoside biosynthesis. Nat. Prod. Rep. 27, 279–304 (2010)." href="/articles/s41467-019-10957-9#ref-CR6" id="ref-link-section-d35905315e2268">6</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 51" title="Esumi, Y. et al. New types of liposidomycins produced by Streptomyces that inhibit bacterial peptidoglycan synthesis. Structure elucidation of fatty acid components by tandem mass spectrometry. J. Antibiot. (Tokyo) 52, 281–287 (1999)." href="/articles/s41467-019-10957-9#ref-CR51" id="ref-link-section-d35905315e2271">51</a></sup>. SAR studies on liposidomycins and the related caprazamycins demonstrate that given a common core structure, varying the aliphatic side chain length does not substantially affect MraY inhibitory activity; however, deacylating the inhibitor altogether leads to decreased activity<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 6" title="Winn, M., Goss, R. J., Kimura, K. & Bugg, T. D. Antimicrobial nucleoside antibiotics targeting cell wall assembly: recent advances in structure-function studies and nucleoside biosynthesis. Nat. Prod. Rep. 27, 279–304 (2010)." href="/articles/s41467-019-10957-9#ref-CR6" id="ref-link-section-d35905315e2275">6</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 31" title="Hirano, S., Ichikawa, S. & Matsuda, A. Structure-activity relationship of truncated analogs of caprazamycins as potential anti-tuberculosis agents. Bioorg. Med. Chem. 16, 5123–5133 (2008)." href="/articles/s41467-019-10957-9#ref-CR31" id="ref-link-section-d35905315e2278">31</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 53" title="Kimura, K.-i & Bugg, T. D. H. Recent advances in antimicrobial nucleoside antibiotics targeting cell wall biosynthesis. Nat. Prod. Rep. 20, 252–273 (2003)." href="/articles/s41467-019-10957-9#ref-CR53" id="ref-link-section-d35905315e2281">53</a></sup>. Carbacaprazamycin has a simplified saturated acyl chain at the 3″ position of the diazepanone moiety (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-019-10957-9#Fig1">1a</a>) instead of the more complex aliphatic moieties observed in the liposidomycins and caprazamycins. This modification makes its chemical synthesis less complicated and improves compound stability, while achieving high in vivo potency, with IC<sub>50</sub> values in the low nanomolar range, and promising activity against <i>S. aureus</i><sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Hirano, S., Ichikawa, S. & Matsuda, A. Synthesis of caprazamycin analogues and their structure–activity relationship for antibacterial activity. J. Org. Chem. 73, 569–577 (2008)." href="/articles/s41467-019-10957-9#ref-CR19" id="ref-link-section-d35905315e2293">19</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Ichikawa, S., Yamaguchi, M., Hsuan, L. S., Kato, Y. & Matsuda, A. Carbacaprazamycins: chemically stable analogues of the caprazamycin nucleoside antibiotics. ACS Infect. Dis. 1, 151–156 (2015)." href="/articles/s41467-019-10957-9#ref-CR26" id="ref-link-section-d35905315e2296">26</a></sup>.</p><p>In light of the MraY<sub>AA</sub>-mureidomycin and MraY<sub>CB</sub>-tunicamycin complex structures, targeting HS5, the magnesium-coordinating residue in MraY, is a generalizable strategy for designing MraY nucleoside inhibitors. Although no known nucleoside inhibitors appear to access the other two aspartate residues of the conserved DDD motif required for MraY catalysis, these residues are in close proximity to D265 (Supplementary Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM1">9</a>), and could be targeted.</p><p>Our structural findings have been summarized in a barcode system for each MraY nucleoside inhibitor (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-019-10957-9#Fig6">6c</a>), which can be used to design novel MraY inhibitors with improved pharmacological properties. One general and obvious strategy to develop new potent MraY inhibitors may be to introduce additional pharmacophores into existing nucleoside MraY inhibitors in order to capture interactions with additional HSs and to engineer favorable pharmacological properties into MraY-targeted inhibitors. SAR studies of muraymycin analogs with various aliphatic tail moieties<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Koppermann, S. et al. Insights into the target interaction of naturally occurring muraymycin nucleoside antibiotics. ChemMedChem 13, 779–784 (2018)." href="/articles/s41467-019-10957-9#ref-CR5" id="ref-link-section-d35905315e2316">5</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 28" title="Tanino, T. et al. Mechanistic analysis of muraymycin analogues: a guide to the design of MraY inhibitors. J. Med. Chem. 54, 8421–8439 (2011)." href="/articles/s41467-019-10957-9#ref-CR28" id="ref-link-section-d35905315e2319">28</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 54" title="Tanino, T. et al. Synthesis and biological evaluation of muraymycin analogues active against anti-drug-resistant bacteria. ACS Med. Chem. Lett. 1, 258–262 (2010)." href="/articles/s41467-019-10957-9#ref-CR54" id="ref-link-section-d35905315e2322">54</a></sup> could provide insight into the feasibility of this approach. Such muraymycin analogs likely occupy HS4, the hydrophobic groove, in addition to the interactions muraymycin D2 makes with the uracil pocket, HS1, and HS2. While the already high in vitro inhibitory potency of these muraymycin analogs is not further enhanced by acylation, the in vivo potency of some acylated muramycins is substantially improved, presumably due to increased membrane permeability<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Koppermann, S. et al. Insights into the target interaction of naturally occurring muraymycin nucleoside antibiotics. ChemMedChem 13, 779–784 (2018)." href="/articles/s41467-019-10957-9#ref-CR5" id="ref-link-section-d35905315e2326">5</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 28" title="Tanino, T. et al. Mechanistic analysis of muraymycin analogues: a guide to the design of MraY inhibitors. J. Med. Chem. 54, 8421–8439 (2011)." href="/articles/s41467-019-10957-9#ref-CR28" id="ref-link-section-d35905315e2329">28</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 54" title="Tanino, T. et al. Synthesis and biological evaluation of muraymycin analogues active against anti-drug-resistant bacteria. ACS Med. Chem. Lett. 1, 258–262 (2010)." href="/articles/s41467-019-10957-9#ref-CR54" id="ref-link-section-d35905315e2332">54</a></sup>. A new strategy is to use the barcode system as a guide to design an MraY inhibitor that targets a novel combination of HSs, which may generate a new type of nucleoside MraY inhibitor with different pharmacological profiles. In principle, a synthetic nucleoside inhibitor targeting all HS1–5 could be developed.</p></div></div></section><section data-title="Methods"><div class="c-article-section" id="Sec13-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec13">Methods</h2><div class="c-article-section__content" id="Sec13-content"><h3 class="c-article__sub-heading" id="Sec14">Nanobody screening</h3><p>MraY<sub>AA</sub> nanobodies were raised by phage display technology using immunized llama as a repertoire source in partnership with Creative Biolabs. MraY<sub>AA</sub> was purified for llama inoculation according to previously reported methods<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Chung, B. C. et al. Crystal structure of MraY, an essential membrane enzyme for bacterial cell wall synthesis. Science 341, 1012–1016 (2013)." href="/articles/s41467-019-10957-9#ref-CR17" id="ref-link-section-d35905315e2352">17</a></sup> with some modifications, described as follows. Fractions eluted from cobalt resin containing MraY<sub>AA</sub> were pooled and heat-treated at 60 °C for 20 min. Contaminating protein precipitated and was pelleted by centrifugation (2900 × <i>g</i>, 5 min). The supernatant was concentrated using 50 kDa molecular weight cutoff centrifugation filters (Millipore) and purified by gel filtration using a Superdex 200 10/300 GL column (GE Healthcare Life Sciences) equilibrated with a buffer containing 20 mM Tris-HCl, 150 mM NaCl, 2 mM dithiothreitol (DTT), 5 mM n-decyl-β-D-maltopyranoside (DM; Anatrace). Peak fractions containing MraY<sub>AA</sub> were collected, pooled, and the concentration of MraY<sub>AA</sub> was determined by OD<sub>280</sub> measurement. Amphipol A8–35 (Anatrace) was added to the protein at a 15× higher concentration than protein. The protein sample containing both detergent and amphipol was incubated at 4 °C with rotation for 4 h. Detergent was removed from the sample using Bio-Beads SM2 (15 mg/mL; Bio-Rad), which were incubated with the protein sample at 4 °C overnight with rotation. The following day, the sample was purified by size exclusion chromatography (SEC) on a Superdex 200 10/300 GL column in phosphate-buffered saline (PBS), pH 7.5. Peak fractions containing MraY<sub>AA</sub> reconstituted in amphipol were pooled, concentrated to 1 mg/mL and sent to Creative Biolabs for immunization.</p><p>Sixty-six unique nanobody sequences were identified and clustered based on their sequence similarity. Representative sequences from each of the clusters, codon-optimized for expression in <i>Escherichia coli</i>, were synthesized into an expression vector with a His<sub>6×</sub> tag and pelB sequence (BioBasic). Of the 23 unique nanobodies, 18 produced protein in a trial expression test. Expression of the 18 nanobodies was then scaled up for protein purification. Nanobody expression plasmids were transformed into C41-DE3 <i>E. coli</i> cells, which were used to inoculate 6 L of Terrific Broth (TB; Fischer Scientific). The cultures were incubated with shaking for ~2 h at 37 °C with shaking until an OD<sub>600</sub> of 0.5 was reached, at which point protein expression was induced with 1 mM IPTG and further incubated at 25 °C overnight (~18 h). Cells were then harvested by centrifugation (6000 × <i>g</i>, 10 min) and resuspended in buffer containing 50 mM Tris-HCl pH 8, 150 mM NaCl, and 20% sucrose. The resuspended cells were rotated for 30 min at room temperature after which they were centrifuged at 13,000 × <i>g</i> for 10 min. The pellet was retained, rapidly resuspended with ice cold buffer (50 mM Tris-HCl pH 8 and 150 mM NaCl), and rotated for 30 min at 4 °C. The sample was then centrifuged (13,000 × g, 10 min) and to the clarified supernatant, 1 mM phenylmethylsulfonyl fluoride (PMSF) and DNase I (20 mg) were added. The mixture was then incubated with cobalt resin (Talon) at 4 °C with rotation for 1 h and the protein was eluted with 200 mM imidazole. Nanobodies were further purified by size exclusion chromatography on a Superdex 200 10/300 GL column equilibrated with 50 mM Tris-HCl pH 8 and 150 mM NaCl.</p><h3 class="c-article__sub-heading" id="Sec15">Protein purification and crystallization</h3><p>The 17 nanobodies that formed a complex with MraY<sub>AA</sub> were screened in crystallization trials in the presence of inhibitors. To prepare MraY<sub>AA</sub>-nanobody protein complex samples for crystallization, nanobodies were expressed and purified as described above and MraY<sub>AA</sub> was prepared as reported<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Chung, B. C. et al. Crystal structure of MraY, an essential membrane enzyme for bacterial cell wall synthesis. Science 341, 1012–1016 (2013)." href="/articles/s41467-019-10957-9#ref-CR17" id="ref-link-section-d35905315e2404">17</a></sup>. Briefly, the gene corresponding to MraY<sub>AA</sub> was codon-optimized for expression in <i>E. coli</i> and synthesized as a fusion with a decahistidine-maltose binding protein (His-MBP) with a PreScission protease site between MraY<sub>AA</sub> and His-MBP. MraY<sub>AA</sub> was expressed in C41 (DE3) cells at 37 °C for 4 h. The His-MBP fusion protein was extracted with dodecyl-maltoside (DDM) and purified using a Co<sup>2+</sup> affinity resin (Talon). His-MBP was cleaved from MraY<sub>AA</sub> by PreScission protease treatment at 4 °C overnight. MraY<sub>AA</sub> was combined with each nanobody at a 1:1.5 molar ratio and the complex was purified by SEC with a Superdex 200 10/300 GL column in 20 mM Tris-HCl, 150 mM NaCl, and 5 mM DM. The peak fractions containing the MraY<sub>AA</sub>-nanobody complex were harvested, concentrated to ~450 μM, and combined with capuramycin, carbacaprazamycin, or 3′-hydroxymureidomycin A at 1:1.5–1:3 molar ratio of protein to inhibitor. All MraY<sub>AA</sub>-nanobody-inhibitor complexes were screened for crystallization via sitting drop vapor diffusion using MemGold<sup>TM</sup> (Molecular Dimensions) and in-house crystallization screening solutions. Of the 17 nanobody complexes screened, 15 produced crystals that were tested for diffraction. One nanobody in particular, NB7, produced the best diffracting crystals in the presence of each of the inhibitors tested. For the MraY<sub>AA</sub>-NB7-carbacaprazamycin complex, crystals formed at 17 °C in 20% polyethelyene glycol (PEG) 4000, 0.2 M potassium thiocyanate, 0.1 M sodium acetate pH 4.6. For the MraY<sub>AA</sub>-NB7-capuramycin complex, crystals formed at 17 °C in 18% PEG 4000, 0.4 M ammonium thiocyanate, 0.1 M sodium acetate pH 4.6. For the MraY<sub>AA</sub>-NB7–3′-hydroxymureidomycin A complex, crystals formed at 17 °C in 20% PEG 4000, 0.2 M ammonium thiocyanate, 0.1 M sodium acetate pH 4.6. All crystals were equilibrated to 4 °C for 24 h prior to harvesting and flash cooling.</p><h3 class="c-article__sub-heading" id="Sec16">Data collection and structure determination</h3><p>X-ray crystal diffraction data were collected on the SERCAT 22-ID and NECAT 24-IDC and 24-ID-E beamlines (Advanced Photo Source, Argonne National Laboratory) using a wavelength of 1.00 or 0.979 Å. All datasets were processed with XDS<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 55" title="Kabsch, W. XDS. Acta Crystallogr. D. Biol. Crystallogr. 66, 125–132 (2010)." href="/articles/s41467-019-10957-9#ref-CR55" id="ref-link-section-d35905315e2445">55</a></sup>. For each inhibitor-bound MraY<sub>AA</sub> structure, datasets from multiple isomorphous crystals were merged using BLEND<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 56" title="Foadi, J. et al. Clustering procedures for the optimal selection of data sets from multiple crystals in macromolecular crystallography. Acta Crystallogr. D. Biol. Crystallogr. 69, 1617–1632 (2013)." href="/articles/s41467-019-10957-9#ref-CR56" id="ref-link-section-d35905315e2451">56</a></sup>. For the merged data of MraY<sub>AA</sub> in complex with 3′-hydroxymureidomycin A, diffraction anisotropy was corrected by ellipsoidal truncation using the STARANISO server<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 57" title="Tickle, I. J. et al. STARANISO. Global Phasing, Inc. (2019). 
 http://staraniso.globalphasing.org/cgi-bin/staraniso.cgi
 
 ." href="/articles/s41467-019-10957-9#ref-CR57" id="ref-link-section-d35905315e2457">57</a></sup>. Phasing for each structure was obtained by molecular replacement in PHASER<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 58" title="McCoy, A. J. et al. Phaser crystallographic software. J. Appl. Crystallogr. 40, 658–674 (2007)." href="/articles/s41467-019-10957-9#ref-CR58" id="ref-link-section-d35905315e2462">58</a></sup> using as search models: (1) the structure of MraY<sub>AA</sub>-muraymycin D2 (PDB ID: 5CKR) with the inhibitor, TM9b, Loop E, and the Loop E helix removed, and (2) a high-resolution structure of a nanobody deposited in the Protein Data Bank (PDB ID: 4C57). The crystals obtained of MraY<sub>AA</sub> in complex with NB7 and each inhibitor were in the P21 space group with two MraY<sub>AA</sub> dimers and 4 NB7 molecules in the asymmetric unit. Inhibitor density was strongest in one MraY<sub>AA</sub> protomer in each structure, probably owing to nanobody crystal packing at this site. Manual model building was performed in COOT<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 59" title="Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D Biol. Crystallogr. 66, 486–501 (2010)." href="/articles/s41467-019-10957-9#ref-CR59" id="ref-link-section-d35905315e2474">59</a></sup> and refinement in PHENIX.refine<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 60" title="Afonine, P. V. et al. Towards automated crystallographic structure refinement with phenix.refine. Acta Crystallogr. D Biol. Crystallogr. 68, 352–367 (2012)." href="/articles/s41467-019-10957-9#ref-CR60" id="ref-link-section-d35905315e2479">60</a></sup>. For the initial molecular replacement solution of MraY<sub>AA</sub> in complex with 3′-hydroxymureidomycin A, jelly-body refinement was first performed using LORESTR<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 61" title="Kovalevskiy, O., Nicholls, R. A. & Murshudov, G. N. Automated refinement of macromolecular structures at low resolution using prior information. Acta Crystallogr. D Struct. Biol. 72, 1149–1161 (2016)." href="/articles/s41467-019-10957-9#ref-CR61" id="ref-link-section-d35905315e2485">61</a></sup>. Molecular graphics were generated using PyMOL<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 62" title="The PyMOL Molecular Graphics System. Version 2.0 Schrödinger, LLC." href="/articles/s41467-019-10957-9#ref-CR62" id="ref-link-section-d35905315e2489">62</a></sup>. For the MraY<sub>AA</sub>-capuramycin structure, sequence conservation was mapped onto the protein surface using the ConSurf server<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 63" title="Celniker, G. et al. ConSurf: using evolutionary data to raise testable hypotheses about protein function. Isr. J. Chem. 53, 199–206 (2013)." href="/articles/s41467-019-10957-9#ref-CR63" id="ref-link-section-d35905315e2495">63</a></sup> with 30 MraY orthologs sequences for the alignment. Data collection and refinement statistics are provided in Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/s41467-019-10957-9#Tab1">1</a>.</p><h3 class="c-article__sub-heading" id="Sec17">UMP-Glo assay</h3><p>The UMP-Glo<sup>TM</sup> glycosyltransferase assay<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 64" title="Das, D., Walvoort, M. T., Lukose, V. & Imperiali, B. A rapid and efficient luminescence-based method for assaying phosphoglycosyltransferase enzymes. Sci. Rep. 6, 33412 (2016)." href="/articles/s41467-019-10957-9#ref-CR64" id="ref-link-section-d35905315e2513">64</a></sup> was carried out according to the manufacturer′s specifications (Promega Corporation). For both IC<sub>50</sub> and specific activity measurements, reaction mixtures contained 150 μM UDP-MurNAc-pentapeptide (UM5A) and 250 μM undecaprenyl phosphate (C<sub>55</sub>-P) in a buffer composed of 100 mM Tris-HCl, 500 mM NaCl, 10 mM MgCl<sub>2</sub>, and 20 mM (3-((3-cholamidopropyl) dimethylammonio)−1-propanesulfonate) (CHAPS; Anatrace). The reaction was initiated with MraY<sub>AA</sub> to a final concentration of 50 nM. Reactions were carried out for 5 min at 45 °C. All luminescence measurements were normalized relative to a negative control reaction without enzyme. For IC<sub>50</sub> measurements, the following concentrations were used. Carbacaprazamycin: 0.01, 0.05, 0.1, 0.5, 1, 20, and 220 μM; capuramycin: 0.01, 0.1, 0.5, 1, 2.5, 50, and 375 μM; 3′-hydroxymureidomycin A: 0.01, 0.05, 0.1, 1, 5, 50, and 370 μM. For specific activity measurements, NB7 and each inhibitor were added to a final concentration of 1 μM and 0.5 μM where present. Luminescence measurements were made using a SpectraMax M3 multi-mode microplate reader.</p><h3 class="c-article__sub-heading" id="Sec18">Synthesis of capuramycin</h3><p>Capuramycin was synthesized according to the known procedure<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 65" title="Kurosu, M., Li, K. & Crick, D. C. Concise synthesis of capuramycin. Org. Lett. 11, 2393–2396 (2009)." href="/articles/s41467-019-10957-9#ref-CR65" id="ref-link-section-d35905315e2537">65</a></sup>. <i>β</i>-Uridine was partially protected with BOM and Tr groups to yield 3-((benzyloxy)methyl)-1-((2<i>R</i>,3<i>R</i>,4<i>S</i>,5<i>R</i>)-3,4-dihydroxy-5-((trityloxy)methyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1<i>H</i>,3<i>H</i>)-dione. Conversion of the above intermediate to the corresponding 2-<i>O</i>-acetyl-3-<i>O</i>-methyl-uridine derivative was achieved through mono-methylation, acetylation, and detritylation. Dess–Martin oxidation of the 2-<i>O</i>-acetyl-3-<i>O</i>-methyl-uridine derivative followed by addition of TMSCN to the resulting aldehyde afforded the cyanohydrin ((2<i>R</i>,3<i>R</i>,4<i>R</i>,5<i>R</i>)-2-(3-((benzyloxy)methyl)-2,4-dioxo-3,4-dihydropyrimidin-1(2<i>H</i>)-yl)-5-((<i>S</i>)-cyano(hydroxy)methyl)-4-methoxytetrahydrofuran-3-yl acetate). Coupling of the cyanohydrin and tetraacetyl thio-α-D-mannopyranoside followed by hydrolysis gave the corresponding amide. Selective deacetylation of the primary acetate using I<sub>2</sub> and removal of the uracil BOM group of the amide provided the primary alcohol ((2<i>S</i>,3<i>S</i>,4<i>S</i>)-2-((<i>R</i>)-1-((2<i>S</i>,3<i>R</i>,4<i>R</i>,5<i>R</i>)-4-acetoxy-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2<i>H</i>)-yl)-3-methoxytetrahydrofuran-2-yl)-2-amino-2-oxoethoxy)-6-(hydroxymethyl)-3,4-dihydro-2<i>H</i>-pyran-3,4-diyl diacetate). Parikh–Doering oxidation of the primary alcohol to the <i>α</i>,<i>β</i>-unsaturated aldehyde followed by Pinnick oxidation afforded the corresponding carboxylic acid ((2<i>S</i>,3<i>S</i>,4<i>S</i>)-3,4-diacetoxy-2-((<i>R</i>)-1-((2<i>S</i>,3<i>R</i>,4<i>R</i>,5<i>R</i>)-4-acetoxy-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2<i>H</i>)-yl)-3-methoxytetrahydrofuran-2-yl)-2-amino-2-oxoethoxy)-3,4-dihydro-2<i>H</i>-pyran-6-carboxylic acid). Final coupling of the carboxylic acid with 2-(<i>S</i>)-aminocaprolactam and exhaustive deprotection accomplished the synthesis of capuramycin.</p><h3 class="c-article__sub-heading" id="Sec19">Synthesis of carbacaprazamycin</h3><p>Carbacaprazamycin was synthesized according to a procedure previously reported<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Ichikawa, S., Yamaguchi, M., Hsuan, L. S., Kato, Y. & Matsuda, A. Carbacaprazamycins: chemically stable analogues of the caprazamycin nucleoside antibiotics. ACS Infect. Dis. 1, 151–156 (2015)." href="/articles/s41467-019-10957-9#ref-CR26" id="ref-link-section-d35905315e2678">26</a></sup>. A mixture of (2<i>S</i>,3<i>R</i>)-<i>tert</i>-butyl-3-hydroxymethyl-2-[<i>N</i>-methyl-(1-phenylfluorenyl)amino]hex-5-enoate and 37% aqueous HCHO in THF was irradiated at 150 °C (9 bar). The mixture was concentrated <i>in vacuo</i>, and the residue was purified by silica gel column chromatography to afford (4<i>S</i>,5<i>R</i>)-4-<i>tert</i>-butoxycarbonyl-3-(1-phenylfluorenyl)-1,3-oxadinane. A solution of this compound and AcOH in CH<sub>2</sub>Cl<sub>2</sub> was stirred at room temperature for 15 min. Sodium triacetoxyborohydride was then added to the mixture, which was stirred at room temperature. The mixture was diluted with AcOEt and washed with saturate aqueous NaHCO<sub>3</sub> and saturate aqueous NaCl. The organic layers was dried with Na<sub>2</sub>SO<sub>4</sub>, filtered, and concentrated in vacuo, and the residue was purified by silica gel column chromatography to afford (2<i>-S</i>,3<i>R</i>)-<i>tert</i>-butyl 3-hydroxymethyl-2-[<i>N</i>-methyl-(1-phenylfluorenyl)amino]hex-5-enoate. A mixture of this compound, hexadecene, and Gubbs second catalyst in CH<sub>2</sub>Cl<sub>2</sub> was heated under reflux. The mixture was cooled to room temperature and concentrated in vacuo. The residue was passed through a silica gel pad with 50% AcOEt in hexane as an eluent to give a crude heneicosanate, which was used to the next step. A mixture of the heneicosanate, AcOH and Pd(OH)<sub>2</sub> in MeOH was vigorously stirred under H<sub>2</sub> atmosphere at room temperature. The catalyst was filtered off through a Celite pad, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (75% AcOEt–hexane) to afford (2<i>S</i>,3<i>R</i>)-<i>tert</i>-butyl 3-hydroxymethyl-2-<i>N</i>-methylaminoheneicosanate. A solution of this compoundand imidazole in CH<sub>2</sub>Cl<sub>2</sub> was treated with TBSCl at room temperature. Few drops of MeOH was added to the mixture, which was further stirred for 5 min. The mixture was diluted with AcOEt, which was washed with 0.1 M aqueous HCl, saturate aqueous NaHCO<sub>3</sub> and saturate aqueous NaCl. The organic layers were dried with Na<sub>2</sub>SO<sub>4</sub>, filtered, and concentrated in vacuo to give a crude amine. A mixture of the crude amine and 6-benzyloxycarbonylamino-5-<i>O</i>-[5-<i>tert</i>-butoxycarbonylamino-5-deoxy-2,3-<i>O</i>-(3-pentylidene)-β-D-<i>ribo</i>-pentofuranosyl]-6-deoxy-2,3-<i>O</i>-isopropylidene-1-(uracil-1-yl)-β-D-glycelo-L-<i>talo</i>-heptofuranuronate in THF was treated sequentially with NaHCO<sub>3</sub> and DEPBT at 0 °C, which was allowed to room temperature. The reaction mixture was partitioned between AcOEt and saturated aqueous NaHCO<sub>3</sub>. The organic phase was washed with saturated aqueous NaCl, dried with Na<sub>2</sub>SO<sub>4</sub>, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford <i>N</i>-[(1<i>S</i>,2<i>R</i>)-1-<i>tert</i>-butoxycarbonyl-2-<i>tert</i>-butyldimethylsilyloxymethyleicosanyl]-<i>N</i>-methyl-6-benzyloxycarbonylamino-1-(3-benzyloxymethyluracil-1-yl)-5-<i>O</i>-[5-<i>tert</i>-butoxycarbonylamino-5-deoxy-2,3-<i>O</i>-(3-pentylidene)-β-D-ribofuranosyl]-6-deoxy-2,3-<i>O</i>-isopropylidene-β-D-<i>glycero</i>-L-<i>talo</i>-heptofuranuronamide. A solution of this compound in MeCN was treated with 3HF·Et<sub>3</sub>N at room temperature. The mixture was diluted with AcOEt, which was washed with saturated aqueous NaCl and saturated aqueous NaCl, dried (Na<sub>2</sub>SO<sub>4</sub>), filtered, and concentrated in vacuo to give a crude alcohol. A solution of the alcohol in CH<sub>2</sub>Cl<sub>2</sub> was treated with Dess–Martin periodinane at room temperature. The mixture was diluted with AcOEt, and a mixture of saturated aqueous NaHCO<sub>3</sub> and saturated aqueous Na<sub>2</sub>S<sub>2</sub>O<sub>3</sub> was added. The whole mixture was vigorously stirred, and the organic phase was dried (Na<sub>2</sub>SO<sub>4</sub>), filtered, and concentrated in vacuo to give a crude aldehyde. A mixture of the aldehyde and Pd black in <i>i</i>-PrOH was vigorously stirred under a H<sub>2</sub> atmosphere at room temperature. The catalyst was filtered off through a Celite pad, and the filtrate was concentrated in vacuo. The residue in CH<sub>2</sub>Cl<sub>2</sub> was treated with AcOH and NaBH(OAc)<sub>3</sub>, and the reaction mixture was stirred at room temperature. The mixture was partitioned between AcOEt and saturated aqueous NaHCO<sub>3</sub>. The organic phase was washed with saturated aqueous NaCl, dried (Na<sub>2</sub>SO<sub>4</sub>), filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford a white foam. A solution of this material in 80% aqueous TFA was stirred at room temperature. The volatiles were removed in vacuo to afford carbacaprazamycin.</p><h3 class="c-article__sub-heading" id="Sec20">Reporting summary</h3><p>Further information on research design is available in the <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM3">Nature Research Reporting Summary</a> linked to this article.</p></div></div></section> </div> <div> <section data-title="Data availability"><div class="c-article-section" id="data-availability-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="data-availability">Data availability</h2><div class="c-article-section__content" id="data-availability-content"> <p>Data supporting the findings of this manuscript are available from the corresponding author upon reasonable request. The source data underlying Supplementary Figs. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM4">1</a>b, <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-019-10957-9#MOESM4">2b</a> are provided as a Source Data file. Atomic coordinates and structure factors for the reported crystal structures are deposited in the Protein Data Bank under accession codes <a href="https://www.rcsb.org/structure/6OYH">6OYH</a>, <a href="https://www.rcsb.org/structure/6OYZ">6OYZ</a>, and <a href="https://www.rcsb.org/structure/6OZ6">6OZ6</a>.</p> </div></div></section><div id="MagazineFulltextArticleBodySuffix"><section aria-labelledby="Bib1" data-title="References"><div class="c-article-section" id="Bib1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Bib1">References</h2><div class="c-article-section__content" id="Bib1-content"><div data-container-section="references"><ol class="c-article-references" data-track-component="outbound reference" data-track-context="references section"><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="1."><p class="c-article-references__text" id="ref-CR1">Tackling Drug-Resistant infections Globally: Final Report and Recommendations. <i>Rev. Antimicrob. Resist.</i> (2016). <a href="https://amrreview.org/" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="https://amrreview.org/">https://amrreview.org/</a>.</p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="2."><p class="c-article-references__text" id="ref-CR2">Blair, J. M., Webber, M. A., Baylay, A. J., Ogbolu, D. O. & Piddock, L. J. Molecular mechanisms of antibiotic resistance. <i>Nat. Rev. Microbiol</i> <b>13</b>, 42–51 (2015).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/nrmicro3380" data-track-item_id="10.1038/nrmicro3380" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fnrmicro3380" aria-label="Article reference 2" data-doi="10.1038/nrmicro3380">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC2cXitVSitbzP" aria-label="CAS reference 2">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=25435309" aria-label="PubMed reference 2">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 2" href="http://scholar.google.com/scholar_lookup?&title=Molecular%20mechanisms%20of%20antibiotic%20resistance&journal=Nat.%20Rev.%20Microbiol&doi=10.1038%2Fnrmicro3380&volume=13&pages=42-51&publication_year=2015&author=Blair%2CJM&author=Webber%2CMA&author=Baylay%2CAJ&author=Ogbolu%2CDO&author=Piddock%2CLJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="3."><p class="c-article-references__text" id="ref-CR3">Hering, J., Dunevall, E., Ek, M. & Branden, G. Structural basis for selective inhibition of antibacterial target MraY, a membrane-bound enzyme involved in peptidoglycan synthesis. <i>Drug Discov. Today</i> <b>23</b>, 1426–1435 (2018).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.drudis.2018.05.020" data-track-item_id="10.1016/j.drudis.2018.05.020" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.drudis.2018.05.020" aria-label="Article reference 3" data-doi="10.1016/j.drudis.2018.05.020">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC1cXhtVeisL3F" aria-label="CAS reference 3">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 3" href="http://scholar.google.com/scholar_lookup?&title=Structural%20basis%20for%20selective%20inhibition%20of%20antibacterial%20target%20MraY%2C%20a%20membrane-bound%20enzyme%20involved%20in%20peptidoglycan%20synthesis&journal=Drug%20Disco.%20Today&doi=10.1016%2Fj.drudis.2018.05.020&volume=23&pages=1426-1435&publication_year=2018&author=Hering%2CJ&author=Dunevall%2CE&author=Ek%2CM&author=Branden%2CG"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="4."><p class="c-article-references__text" id="ref-CR4">Koppermann, S. & Ducho, C. Natural Products at Work: structural Insights into Inhibition of the Bacterial Membrane Protein MraY. <i>Angew. Chem. Int. Ed. Engl.</i> <b>55</b>, 11722–11724 (2016).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/anie.201606396" data-track-item_id="10.1002/anie.201606396" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2Fanie.201606396" aria-label="Article reference 4" data-doi="10.1002/anie.201606396">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC28XhtlalsbzM" aria-label="CAS reference 4">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=27511599" aria-label="PubMed reference 4">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 4" href="http://scholar.google.com/scholar_lookup?&title=Natural%20Products%20at%20Work%3A%20structural%20Insights%20into%20Inhibition%20of%20the%20Bacterial%20Membrane%20Protein%20MraY&journal=Angew.%20Chem.%20Int%20Ed.%20Engl.&doi=10.1002%2Fanie.201606396&volume=55&pages=11722-11724&publication_year=2016&author=Koppermann%2CS&author=Ducho%2CC"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="5."><p class="c-article-references__text" id="ref-CR5">Koppermann, S. et al. Insights into the target interaction of naturally occurring muraymycin nucleoside antibiotics. <i>ChemMedChem</i> <b>13</b>, 779–784 (2018).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/cmdc.201700793" data-track-item_id="10.1002/cmdc.201700793" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2Fcmdc.201700793" aria-label="Article reference 5" data-doi="10.1002/cmdc.201700793">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC1cXltlSru7g%3D" aria-label="CAS reference 5">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=29438582" aria-label="PubMed reference 5">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019934" aria-label="PubMed Central reference 5">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 5" href="http://scholar.google.com/scholar_lookup?&title=Insights%20into%20the%20target%20interaction%20of%20naturally%20occurring%20muraymycin%20nucleoside%20antibiotics&journal=ChemMedChem&doi=10.1002%2Fcmdc.201700793&volume=13&pages=779-784&publication_year=2018&author=Koppermann%2CS"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="6."><p class="c-article-references__text" id="ref-CR6">Winn, M., Goss, R. J., Kimura, K. & Bugg, T. D. Antimicrobial nucleoside antibiotics targeting cell wall assembly: recent advances in structure-function studies and nucleoside biosynthesis. <i>Nat. Prod. Rep.</i> <b>27</b>, 279–304 (2010).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1039/B816215H" data-track-item_id="10.1039/B816215H" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1039%2FB816215H" aria-label="Article reference 6" data-doi="10.1039/B816215H">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC3cXht1Sntb8%3D" aria-label="CAS reference 6">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=20111805" aria-label="PubMed reference 6">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 6" href="http://scholar.google.com/scholar_lookup?&title=Antimicrobial%20nucleoside%20antibiotics%20targeting%20cell%20wall%20assembly%3A%20recent%20advances%20in%20structure-function%20studies%20and%20nucleoside%20biosynthesis&journal=Nat.%20Prod.%20Rep.&doi=10.1039%2FB816215H&volume=27&pages=279-304&publication_year=2010&author=Winn%2CM&author=Goss%2CRJ&author=Kimura%2CK&author=Bugg%2CTD"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="7."><p class="c-article-references__text" id="ref-CR7">Ichikawa, S., Yamaguchi, M. & Matsuda, A. Antibacterial nucleoside natural products inhibiting phospho-MurNAc-pentapeptide translocase; chemistry and structure-activity relationship. <i>Curr. Med. Chem.</i> <b>22</b>, 3951–3979 (2015).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.2174/0929867322666150818103502" data-track-item_id="10.2174/0929867322666150818103502" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.2174%2F0929867322666150818103502" aria-label="Article reference 7" data-doi="10.2174/0929867322666150818103502">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC2MXhvFGit7nL" aria-label="CAS reference 7">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=26282943" aria-label="PubMed reference 7">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 7" href="http://scholar.google.com/scholar_lookup?&title=Antibacterial%20nucleoside%20natural%20products%20inhibiting%20phospho-MurNAc-pentapeptide%20translocase%3B%20chemistry%20and%20structure-activity%20relationship&journal=Curr.%20Med%20Chem.&doi=10.2174%2F0929867322666150818103502&volume=22&pages=3951-3979&publication_year=2015&author=Ichikawa%2CS&author=Yamaguchi%2CM&author=Matsuda%2CA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="8."><p class="c-article-references__text" id="ref-CR8">Brandish, P. E. et al. Modes of action of tunicamycin, liposidomycin B, and mureidomycin A: inhibition of phospho-N-acetylmuramyl-pentapeptide translocase from Escherichia coli. <i>Antimicrob. Agents Chemother.</i> <b>40</b>, 1640–1644 (1996).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1128/AAC.40.7.1640" data-track-item_id="10.1128/AAC.40.7.1640" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1128%2FAAC.40.7.1640" aria-label="Article reference 8" data-doi="10.1128/AAC.40.7.1640">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DyaK28XktVaksLw%3D" aria-label="CAS reference 8">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=8807054" aria-label="PubMed reference 8">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC163387" aria-label="PubMed Central reference 8">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 8" href="http://scholar.google.com/scholar_lookup?&title=Modes%20of%20action%20of%20tunicamycin%2C%20liposidomycin%20B%2C%20and%20mureidomycin%20A%3A%20inhibition%20of%20phospho-N-acetylmuramyl-pentapeptide%20translocase%20from%20Escherichia%20coli&journal=Antimicrob.%20Agents%20Chemother.&doi=10.1128%2FAAC.40.7.1640&volume=40&pages=1640-1644&publication_year=1996&author=Brandish%2CPE"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="9."><p class="c-article-references__text" id="ref-CR9">Muramatsu, Y., Ishii, M. M. & Inukai, M. Studies on novel bacterial translocase I inhibitors, A-500359s. II. Biological activities of A-500359 A, C., D. G<i>. J. Antibiot. (Tokyo)</i> <b>56</b>, 253–258 (2003).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD3sXivVSmtbc%3D" aria-label="CAS reference 9">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 9" href="http://scholar.google.com/scholar_lookup?&title=Studies%20on%20novel%20bacterial%20translocase%20I%20inhibitors%2C%20A-500359s.%20II&journal=Biol.%20Act.%20A-500359%20A%2C%20C.%2C%20D.%20G.%20J.%20Antibiot.%20%28Tokyo%29&volume=56&pages=253-258&publication_year=2003&author=Muramatsu%2CY&author=Ishii%2CMM&author=Inukai%2CM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="10."><p class="c-article-references__text" id="ref-CR10">Brandish, P. E. et al. Slow binding inhibition of phospho-N-acetylmuramyl-pentapeptide-translocase (Escherichia coli) by mureidomycin A. <i>J. Biol. Chem.</i> <b>271</b>, 7609–7614 (1996).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1074/jbc.271.13.7609" data-track-item_id="10.1074/jbc.271.13.7609" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1074%2Fjbc.271.13.7609" aria-label="Article reference 10" data-doi="10.1074/jbc.271.13.7609">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DyaK28XhvFyksbo%3D" aria-label="CAS reference 10">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=8631795" aria-label="PubMed reference 10">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 10" href="http://scholar.google.com/scholar_lookup?&title=Slow%20binding%20inhibition%20of%20phospho-N-acetylmuramyl-pentapeptide-translocase%20%28Escherichia%20coli%29%20by%20mureidomycin%20A&journal=J.%20Biol.%20Chem.&doi=10.1074%2Fjbc.271.13.7609&volume=271&pages=7609-7614&publication_year=1996&author=Brandish%2CPE"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="11."><p class="c-article-references__text" id="ref-CR11">Duksin, D. & Mahoney, W. C. Relationship of the structure and biological activity of the natural homologues of tunicamycin. <i>J. Biol. Chem.</i> <b>257</b>, 3105–3109 (1982).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DyaL38Xhs1SitLs%3D" aria-label="CAS reference 11">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=7061468" aria-label="PubMed reference 11">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 11" href="http://scholar.google.com/scholar_lookup?&title=Relationship%20of%20the%20structure%20and%20biological%20activity%20of%20the%20natural%20homologues%20of%20tunicamycin&journal=J.%20Biol.%20Chem.&volume=257&pages=3105-3109&publication_year=1982&author=Duksin%2CD&author=Mahoney%2CWC"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="12."><p class="c-article-references__text" id="ref-CR12">Inukai, M., Isono, F. & Takatsuki, A. Selective inhibition of the bacterial translocase reaction in peptidoglycan synthesis by mureidomycins. <i>Antimicrob. Agents Chemother.</i> <b>37</b>, 980–983 (1993).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1128/AAC.37.5.980" data-track-item_id="10.1128/AAC.37.5.980" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1128%2FAAC.37.5.980" aria-label="Article reference 12" data-doi="10.1128/AAC.37.5.980">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DyaK3sXkt1Sjs7c%3D" aria-label="CAS reference 12">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=8517724" aria-label="PubMed reference 12">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC187869" aria-label="PubMed Central reference 12">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 12" href="http://scholar.google.com/scholar_lookup?&title=Selective%20inhibition%20of%20the%20bacterial%20translocase%20reaction%20in%20peptidoglycan%20synthesis%20by%20mureidomycins&journal=Antimicrob.%20Agents%20Chemother.&doi=10.1128%2FAAC.37.5.980&volume=37&pages=980-983&publication_year=1993&author=Inukai%2CM&author=Isono%2CF&author=Takatsuki%2CA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="13."><p class="c-article-references__text" id="ref-CR13">Hakulinen, J. K. et al. MraY-antibiotic complex reveals details of tunicamycin mode of action. <i>Nat. Chem. Biol.</i> <b>13</b>, 265–267 (2017).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/nchembio.2270" data-track-item_id="10.1038/nchembio.2270" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fnchembio.2270" aria-label="Article reference 13" data-doi="10.1038/nchembio.2270">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC2sXmslClsQ%3D%3D" aria-label="CAS reference 13">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=28068312" aria-label="PubMed reference 13">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 13" href="http://scholar.google.com/scholar_lookup?&title=MraY-antibiotic%20complex%20reveals%20details%20of%20tunicamycin%20mode%20of%20action&journal=Nat.%20Chem.%20Biol.&doi=10.1038%2Fnchembio.2270&volume=13&pages=265-267&publication_year=2017&author=Hakulinen%2CJK"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="14."><p class="c-article-references__text" id="ref-CR14">Yoo, J. et al. GlcNAc-1-P-transferase-tunicamycin complex structure reveals basis for inhibition of N-glycosylation. <i>Nat. Struct. Mol. Biol.</i> <b>25</b>, 217–224 (2018).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41594-018-0031-y" data-track-item_id="10.1038/s41594-018-0031-y" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41594-018-0031-y" aria-label="Article reference 14" data-doi="10.1038/s41594-018-0031-y">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC1cXhtlOjsrzP" aria-label="CAS reference 14">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=29459785" aria-label="PubMed reference 14">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840018" aria-label="PubMed Central reference 14">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 14" href="http://scholar.google.com/scholar_lookup?&title=GlcNAc-1-P-transferase-tunicamycin%20complex%20structure%20reveals%20basis%20for%20inhibition%20of%20N-glycosylation&journal=Nat.%20Struct.%20Mol.%20Biol.&doi=10.1038%2Fs41594-018-0031-y&volume=25&pages=217-224&publication_year=2018&author=Yoo%2CJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="15."><p class="c-article-references__text" id="ref-CR15">Dong, Y. Y. et al. Structures of DPAGT1 explain glycosylation disease mechanisms and advance TB antibiotic design. <i>Cell</i> <b>175</b>, 1045–1058 (2018). e1016.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.cell.2018.10.037" data-track-item_id="10.1016/j.cell.2018.10.037" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.cell.2018.10.037" aria-label="Article reference 15" data-doi="10.1016/j.cell.2018.10.037">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC1cXitVyhurrK" aria-label="CAS reference 15">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=30388443" aria-label="PubMed reference 15">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218659" aria-label="PubMed Central reference 15">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 15" href="http://scholar.google.com/scholar_lookup?&title=Structures%20of%20DPAGT1%20explain%20glycosylation%20disease%20mechanisms%20and%20advance%20TB%20antibiotic%20design&journal=Cell&doi=10.1016%2Fj.cell.2018.10.037&volume=175&pages=1045-1058&publication_year=2018&author=Dong%2CYY"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="16."><p class="c-article-references__text" id="ref-CR16">Perot, S., Sperandio, O., Miteva, M. A., Camproux, A. C. & Villoutreix, B. O. Druggable pockets and binding site centric chemical space: a paradigm shift in drug discovery. <i>Drug Discov. Today</i> <b>15</b>, 656–667 (2010).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.drudis.2010.05.015" data-track-item_id="10.1016/j.drudis.2010.05.015" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.drudis.2010.05.015" aria-label="Article reference 16" data-doi="10.1016/j.drudis.2010.05.015">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC3cXhtVeksb3I" aria-label="CAS reference 16">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 16" href="http://scholar.google.com/scholar_lookup?&title=Druggable%20pockets%20and%20binding%20site%20centric%20chemical%20space%3A%20a%20paradigm%20shift%20in%20drug%20discovery&journal=Drug%20Disco.%20Today&doi=10.1016%2Fj.drudis.2010.05.015&volume=15&pages=656-667&publication_year=2010&author=Perot%2CS&author=Sperandio%2CO&author=Miteva%2CMA&author=Camproux%2CAC&author=Villoutreix%2CBO"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="17."><p class="c-article-references__text" id="ref-CR17">Chung, B. C. et al. Crystal structure of MraY, an essential membrane enzyme for bacterial cell wall synthesis. <i>Science</i> <b>341</b>, 1012–1016 (2013).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1126/science.1236501" data-track-item_id="10.1126/science.1236501" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1126%2Fscience.1236501" aria-label="Article reference 17" data-doi="10.1126/science.1236501">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="ads reference" data-track-action="ads reference" href="http://adsabs.harvard.edu/cgi-bin/nph-data_query?link_type=ABSTRACT&bibcode=2013Sci...341.1012C" aria-label="ADS reference 17">ADS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC3sXhtlaktbnE" aria-label="CAS reference 17">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23990562" aria-label="PubMed reference 17">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3906829" aria-label="PubMed Central reference 17">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 17" href="http://scholar.google.com/scholar_lookup?&title=Crystal%20structure%20of%20MraY%2C%20an%20essential%20membrane%20enzyme%20for%20bacterial%20cell%20wall%20synthesis&journal=Science&doi=10.1126%2Fscience.1236501&volume=341&pages=1012-1016&publication_year=2013&author=Chung%2CBC"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="18."><p class="c-article-references__text" id="ref-CR18">Chung, B. C. et al. Structural insights into inhibition of lipid I production in bacterial cell wall synthesis. <i>Nature</i> <b>533</b>, 557–560 (2016).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/nature17636" data-track-item_id="10.1038/nature17636" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fnature17636" aria-label="Article reference 18" data-doi="10.1038/nature17636">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="ads reference" data-track-action="ads reference" href="http://adsabs.harvard.edu/cgi-bin/nph-data_query?link_type=ABSTRACT&bibcode=2016Natur.533..557C" aria-label="ADS reference 18">ADS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC28Xmt1eku70%3D" aria-label="CAS reference 18">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=27088606" aria-label="PubMed reference 18">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4882255" aria-label="PubMed Central reference 18">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 18" href="http://scholar.google.com/scholar_lookup?&title=Structural%20insights%20into%20inhibition%20of%20lipid%20I%20production%20in%20bacterial%20cell%20wall%20synthesis&journal=Nature&doi=10.1038%2Fnature17636&volume=533&pages=557-560&publication_year=2016&author=Chung%2CBC"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="19."><p class="c-article-references__text" id="ref-CR19">Hirano, S., Ichikawa, S. & Matsuda, A. Synthesis of caprazamycin analogues and their structure–activity relationship for antibacterial activity. <i>J. Org. Chem.</i> <b>73</b>, 569–577 (2008).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1021/jo702264e" data-track-item_id="10.1021/jo702264e" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1021%2Fjo702264e" aria-label="Article reference 19" data-doi="10.1021/jo702264e">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD2sXhsVCisL3L" aria-label="CAS reference 19">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=18092805" aria-label="PubMed reference 19">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 19" href="http://scholar.google.com/scholar_lookup?&title=Synthesis%20of%20caprazamycin%20analogues%20and%20their%20structure%E2%80%93activity%20relationship%20for%20antibacterial%20activity&journal=J.%20Org.%20Chem.&doi=10.1021%2Fjo702264e&volume=73&pages=569-577&publication_year=2008&author=Hirano%2CS&author=Ichikawa%2CS&author=Matsuda%2CA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="20."><p class="c-article-references__text" id="ref-CR20">Isono, F., Katayama, T., Inukai, M., Haneishi, T. & Mureidomycins, A.-D. novel peptidylnucleoside antibiotics with spheroplast forming activity. III. Biological properties<i>. J. Antibiot. (Tokyo)</i> <b>42</b>, 674–679 (1989).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.7164/antibiotics.42.674" data-track-item_id="10.7164/antibiotics.42.674" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.7164%2Fantibiotics.42.674" aria-label="Article reference 20" data-doi="10.7164/antibiotics.42.674">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DyaL1MXksFCjt7o%3D" aria-label="CAS reference 20">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 20" href="http://scholar.google.com/scholar_lookup?&title=novel%20peptidylnucleoside%20antibiotics%20with%20spheroplast%20forming%20activity.%20III&journal=Biol.%20Prop.%20J.%20Antibiot.%20%28Tokyo%29&doi=10.7164%2Fantibiotics.42.674&volume=42&pages=674-679&publication_year=1989&author=Isono%2CF&author=Katayama%2CT&author=Inukai%2CM&author=Haneishi%2CT&author=Mureidomycins%2CA-D"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="21."><p class="c-article-references__text" id="ref-CR21">Isono, F., Kodama, K. & Inukai, M. Susceptibility of Pseudomonas species to the novel antibiotics mureidomycins. <i>Antimicrob. Agents Chemother.</i> <b>36</b>, 1024–1027 (1992).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1128/AAC.36.5.1024" data-track-item_id="10.1128/AAC.36.5.1024" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1128%2FAAC.36.5.1024" aria-label="Article reference 21" data-doi="10.1128/AAC.36.5.1024">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DyaK38XktVCisrs%3D" aria-label="CAS reference 21">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=1510388" aria-label="PubMed reference 21">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC188829" aria-label="PubMed Central reference 21">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 21" href="http://scholar.google.com/scholar_lookup?&title=Susceptibility%20of%20Pseudomonas%20species%20to%20the%20novel%20antibiotics%20mureidomycins&journal=Antimicrob.%20Agents%20Chemother.&doi=10.1128%2FAAC.36.5.1024&volume=36&pages=1024-1027&publication_year=1992&author=Isono%2CF&author=Kodama%2CK&author=Inukai%2CM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="22."><p class="c-article-references__text" id="ref-CR22">Hotoda, H. et al. Synthesis and antimycobacterial activity of capuramycin analogues. Part 1: substitution of the azepan-2-one moiety of capuramycin. <i>Bioorg. Med. Chem. Lett.</i> <b>13</b>, 2829–2832 (2003).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/S0960-894X(03)00596-1" data-track-item_id="10.1016/S0960-894X(03)00596-1" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2FS0960-894X%2803%2900596-1" aria-label="Article reference 22" data-doi="10.1016/S0960-894X(03)00596-1">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD3sXmvFajtb0%3D" aria-label="CAS reference 22">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=14611838" aria-label="PubMed reference 22">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 22" href="http://scholar.google.com/scholar_lookup?&title=Synthesis%20and%20antimycobacterial%20activity%20of%20capuramycin%20analogues.%20Part%201%3A%20substitution%20of%20the%20azepan-2-one%20moiety%20of%20capuramycin&journal=Bioorg.%20Med%20Chem.%20Lett.&doi=10.1016%2FS0960-894X%2803%2900596-1&volume=13&pages=2829-2832&publication_year=2003&author=Hotoda%2CH"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="23."><p class="c-article-references__text" id="ref-CR23">Hotoda, H. et al. Synthesis and antimycobacterial activity of capuramycin analogues. Part 2: acylated derivatives of capuramycin-related compounds. <i>Bioorg. Med. Chem. Lett.</i> <b>13</b>, 2833–2836 (2003).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/S0960-894X(03)00597-3" data-track-item_id="10.1016/S0960-894X(03)00597-3" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2FS0960-894X%2803%2900597-3" aria-label="Article reference 23" data-doi="10.1016/S0960-894X(03)00597-3">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD3sXmvFajtbo%3D" aria-label="CAS reference 23">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=14611839" aria-label="PubMed reference 23">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 23" href="http://scholar.google.com/scholar_lookup?&title=Synthesis%20and%20antimycobacterial%20activity%20of%20capuramycin%20analogues.%20Part%202%3A%20acylated%20derivatives%20of%20capuramycin-related%20compounds&journal=Bioorg.%20Med%20Chem.%20Lett.&doi=10.1016%2FS0960-894X%2803%2900597-3&volume=13&pages=2833-2836&publication_year=2003&author=Hotoda%2CH"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="24."><p class="c-article-references__text" id="ref-CR24">Reddy, V. M., Einck, L. & Nacy, C. A. In vitro antimycobacterial activities of capuramycin analogues. <i>Antimicrob. Agents Chemother.</i> <b>52</b>, 719–721 (2008).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1128/AAC.01469-07" data-track-item_id="10.1128/AAC.01469-07" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1128%2FAAC.01469-07" aria-label="Article reference 24" data-doi="10.1128/AAC.01469-07">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD1cXhtlWjs70%3D" aria-label="CAS reference 24">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=18070956" aria-label="PubMed reference 24">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 24" href="http://scholar.google.com/scholar_lookup?&title=In%20vitro%20antimycobacterial%20activities%20of%20capuramycin%20analogues&journal=Antimicrob.%20Agents%20Chemother.&doi=10.1128%2FAAC.01469-07&volume=52&pages=719-721&publication_year=2008&author=Reddy%2CVM&author=Einck%2CL&author=Nacy%2CCA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="25."><p class="c-article-references__text" id="ref-CR25">Kimura, K.-i et al. Liposidomycin C inhibits phospho-N-acetylmuramyl-pentapeptide transferase in peptidoglycan synthesis of Escherichia coli Y-10. <i>Agric. Biol. Chem.</i> <b>53</b>, 1811–1815 (1989).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DyaL1MXlslSqtLo%3D" aria-label="CAS reference 25">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 25" href="http://scholar.google.com/scholar_lookup?&title=Liposidomycin%20C%20inhibits%20phospho-N-acetylmuramyl-pentapeptide%20transferase%20in%20peptidoglycan%20synthesis%20of%20Escherichia%20coli%20Y-10&journal=Agric.%20Biol.%20Chem.&volume=53&pages=1811-1815&publication_year=1989&author=Kimura%2CK-i"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="26."><p class="c-article-references__text" id="ref-CR26">Ichikawa, S., Yamaguchi, M., Hsuan, L. S., Kato, Y. & Matsuda, A. Carbacaprazamycins: chemically stable analogues of the caprazamycin nucleoside antibiotics. <i>ACS Infect. Dis.</i> <b>1</b>, 151–156 (2015).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1021/id5000376" data-track-item_id="10.1021/id5000376" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1021%2Fid5000376" aria-label="Article reference 26" data-doi="10.1021/id5000376">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC2MXjtVahsbg%3D" aria-label="CAS reference 26">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=27622529" aria-label="PubMed reference 26">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 26" href="http://scholar.google.com/scholar_lookup?&title=Carbacaprazamycins%3A%20chemically%20stable%20analogues%20of%20the%20caprazamycin%20nucleoside%20antibiotics&journal=ACS%20Infect.%20Dis.&doi=10.1021%2Fid5000376&volume=1&pages=151-156&publication_year=2015&author=Ichikawa%2CS&author=Yamaguchi%2CM&author=Hsuan%2CLS&author=Kato%2CY&author=Matsuda%2CA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="27."><p class="c-article-references__text" id="ref-CR27">Isono, F. & Inukai, M. Mureidomycin A, a new inhibitor of bacterial peptidoglycan synthesis. <i>Antimicrob. Agents Chemother.</i> <b>35</b>, 234–236 (1991).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1128/AAC.35.2.234" data-track-item_id="10.1128/AAC.35.2.234" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1128%2FAAC.35.2.234" aria-label="Article reference 27" data-doi="10.1128/AAC.35.2.234">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DyaK3MXhs1SmurY%3D" aria-label="CAS reference 27">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=1902646" aria-label="PubMed reference 27">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC244983" aria-label="PubMed Central reference 27">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 27" href="http://scholar.google.com/scholar_lookup?&title=Mureidomycin%20A%2C%20a%20new%20inhibitor%20of%20bacterial%20peptidoglycan%20synthesis&journal=Antimicrob.%20Agents%20Chemother.&doi=10.1128%2FAAC.35.2.234&volume=35&pages=234-236&publication_year=1991&author=Isono%2CF&author=Inukai%2CM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="28."><p class="c-article-references__text" id="ref-CR28">Tanino, T. et al. Mechanistic analysis of muraymycin analogues: a guide to the design of MraY inhibitors. <i>J. Med. Chem.</i> <b>54</b>, 8421–8439 (2011).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1021/jm200906r" data-track-item_id="10.1021/jm200906r" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1021%2Fjm200906r" aria-label="Article reference 28" data-doi="10.1021/jm200906r">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC3MXhsVOlt73O" aria-label="CAS reference 28">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=22085339" aria-label="PubMed reference 28">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 28" href="http://scholar.google.com/scholar_lookup?&title=Mechanistic%20analysis%20of%20muraymycin%20analogues%3A%20a%20guide%20to%20the%20design%20of%20MraY%20inhibitors&journal=J.%20Med.%20Chem.&doi=10.1021%2Fjm200906r&volume=54&pages=8421-8439&publication_year=2011&author=Tanino%2CT"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="29."><p class="c-article-references__text" id="ref-CR29">Yamamoto, K., Katsuyama, A. & Ichikawa, S. Structural requirement of tunicamycin V for MraY inhibition. <i>Bioorg. Med. Chem. Lett.</i> <b>27</b>, 1714–1719 (2019).</p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="30."><p class="c-article-references__text" id="ref-CR30">Hirano, S., Ichikawa, S. & Matsuda, A. Design and synthesis of diketopiperazine and acyclic analogs related to the caprazamycins and liposidomycins as potential antibacterial agents. <i>Bioorg. Med. Chem.</i> <b>16</b>, 428–436 (2008).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.bmc.2007.09.022" data-track-item_id="10.1016/j.bmc.2007.09.022" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.bmc.2007.09.022" aria-label="Article reference 30" data-doi="10.1016/j.bmc.2007.09.022">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD1cXlvFSktA%3D%3D" aria-label="CAS reference 30">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=17904373" aria-label="PubMed reference 30">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 30" href="http://scholar.google.com/scholar_lookup?&title=Design%20and%20synthesis%20of%20diketopiperazine%20and%20acyclic%20analogs%20related%20to%20the%20caprazamycins%20and%20liposidomycins%20as%20potential%20antibacterial%20agents&journal=Bioorg.%20Med%20Chem.&doi=10.1016%2Fj.bmc.2007.09.022&volume=16&pages=428-436&publication_year=2008&author=Hirano%2CS&author=Ichikawa%2CS&author=Matsuda%2CA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="31."><p class="c-article-references__text" id="ref-CR31">Hirano, S., Ichikawa, S. & Matsuda, A. Structure-activity relationship of truncated analogs of caprazamycins as potential anti-tuberculosis agents. <i>Bioorg. Med. Chem.</i> <b>16</b>, 5123–5133 (2008).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.bmc.2008.03.020" data-track-item_id="10.1016/j.bmc.2008.03.020" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.bmc.2008.03.020" aria-label="Article reference 31" data-doi="10.1016/j.bmc.2008.03.020">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD1cXlvVSqtbw%3D" aria-label="CAS reference 31">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=18375127" aria-label="PubMed reference 31">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 31" href="http://scholar.google.com/scholar_lookup?&title=Structure-activity%20relationship%20of%20truncated%20analogs%20of%20caprazamycins%20as%20potential%20anti-tuberculosis%20agents&journal=Bioorg.%20Med%20Chem.&doi=10.1016%2Fj.bmc.2008.03.020&volume=16&pages=5123-5133&publication_year=2008&author=Hirano%2CS&author=Ichikawa%2CS&author=Matsuda%2CA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="32."><p class="c-article-references__text" id="ref-CR32">Muramatsu, Y. et al. Studies on novel bacterial translocase I inhibitors, A-500359s. III. Deaminocaprolactam derivatives of capuramycin: A-500359 E, F, H; M-1 and M-2. <i>J. Antibiot. (Tokyo)</i> <b>56</b>, 259–267 (2003).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.7164/antibiotics.56.259" data-track-item_id="10.7164/antibiotics.56.259" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.7164%2Fantibiotics.56.259" aria-label="Article reference 32" data-doi="10.7164/antibiotics.56.259">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD3sXivVSmur4%3D" aria-label="CAS reference 32">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 32" href="http://scholar.google.com/scholar_lookup?&title=Studies%20on%20novel%20bacterial%20translocase%20I%20inhibitors%2C%20A-500359s.%20III.%20Deaminocaprolactam%20derivatives%20of%20capuramycin%3A%20A-500359%20E%2C%20F%2C%20H%3B%20M-1%20and%20M-2&journal=J.%20Antibiot.%20%28Tokyo%29&doi=10.7164%2Fantibiotics.56.259&volume=56&pages=259-267&publication_year=2003&author=Muramatsu%2CY"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="33."><p class="c-article-references__text" id="ref-CR33">Okamoto, K. et al. Total synthesis and biological evaluation of pacidamycin D and its 3′-hydroxy analogue. <i>J. Org. Chem.</i> <b>77</b>, 1367–1377 (2012).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1021/jo202159q" data-track-item_id="10.1021/jo202159q" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1021%2Fjo202159q" aria-label="Article reference 33" data-doi="10.1021/jo202159q">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC3MXhs1GlsL%2FE" aria-label="CAS reference 33">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=22196045" aria-label="PubMed reference 33">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 33" href="http://scholar.google.com/scholar_lookup?&title=Total%20synthesis%20and%20biological%20evaluation%20of%20pacidamycin%20D%20and%20its%203%E2%80%B2-hydroxy%20analogue&journal=J.%20Org.%20Chem.&doi=10.1021%2Fjo202159q&volume=77&pages=1367-1377&publication_year=2012&author=Okamoto%2CK"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="34."><p class="c-article-references__text" id="ref-CR34">Dini, C. et al. Synthesis of analogues of the O-beta-D-ribofuranosyl nucleoside moiety of liposidomycins. Part 1: contribution of the amino group and the uracil moiety upon the inhibition of MraY. <i>Bioorg. Med. Chem. Lett.</i> <b>11</b>, 529–531 (2001).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/S0960-894X(00)00715-0" data-track-item_id="10.1016/S0960-894X(00)00715-0" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2FS0960-894X%2800%2900715-0" aria-label="Article reference 34" data-doi="10.1016/S0960-894X(00)00715-0">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD3MXhslOnsrY%3D" aria-label="CAS reference 34">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=11229763" aria-label="PubMed reference 34">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 34" href="http://scholar.google.com/scholar_lookup?&title=Synthesis%20of%20analogues%20of%20the%20O-beta-D-ribofuranosyl%20nucleoside%20moiety%20of%20liposidomycins.%20Part%201%3A%20contribution%20of%20the%20amino%20group%20and%20the%20uracil%20moiety%20upon%20the%20inhibition%20of%20MraY&journal=Bioorg.%20Med%20Chem.%20Lett.&doi=10.1016%2FS0960-894X%2800%2900715-0&volume=11&pages=529-531&publication_year=2001&author=Dini%2CC"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="35."><p class="c-article-references__text" id="ref-CR35">Isono, F. et al. Mureidomycins E and F, minor components of mureidomycins. <i>J. Antibiot. (Tokyo)</i> <b>46</b>, 1203–1207 (1993).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.7164/antibiotics.46.1203" data-track-item_id="10.7164/antibiotics.46.1203" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.7164%2Fantibiotics.46.1203" aria-label="Article reference 35" data-doi="10.7164/antibiotics.46.1203">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="ads reference" data-track-action="ads reference" href="http://adsabs.harvard.edu/cgi-bin/nph-data_query?link_type=ABSTRACT&bibcode=1993taap.conf.....I" aria-label="ADS reference 35">ADS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DyaK2cXjtVGrtg%3D%3D" aria-label="CAS reference 35">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 35" href="http://scholar.google.com/scholar_lookup?&title=Mureidomycins%20E%20and%20F%2C%20minor%20components%20of%20mureidomycins&journal=J.%20Antibiot.%20%28Tokyo%29&doi=10.7164%2Fantibiotics.46.1203&volume=46&pages=1203-1207&publication_year=1993&author=Isono%2CF"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="36."><p class="c-article-references__text" id="ref-CR36">Chatterjee, S. et al. Napsamycins, new Pseudomonas active antibiotics of the mureidomycin family from Streptomyces sp. HIL Y-82,11372. <i>J. Antibiot. (Tokyo)</i> <b>47</b>, 595–598 (1994).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.7164/antibiotics.47.595" data-track-item_id="10.7164/antibiotics.47.595" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.7164%2Fantibiotics.47.595" aria-label="Article reference 36" data-doi="10.7164/antibiotics.47.595">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DyaK2cXlt12msrg%3D" aria-label="CAS reference 36">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 36" href="http://scholar.google.com/scholar_lookup?&title=Napsamycins%2C%20new%20Pseudomonas%20active%20antibiotics%20of%20the%20mureidomycin%20family%20from%20Streptomyces%20sp.%20HIL%20Y-82%2C11372&journal=J.%20Antibiot.%20%28Tokyo%29&doi=10.7164%2Fantibiotics.47.595&volume=47&pages=595-598&publication_year=1994&author=Chatterjee%2CS"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="37."><p class="c-article-references__text" id="ref-CR37">McDonald, L. A. et al. Structures of the muraymycins, novel peptidoglycan biosynthesis inhibitors. <i>J. Am. Chem. Soc.</i> <b>124</b>, 10260–10261 (2002).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1021/ja017748h" data-track-item_id="10.1021/ja017748h" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1021%2Fja017748h" aria-label="Article reference 37" data-doi="10.1021/ja017748h">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD38XlvFGmu7c%3D" aria-label="CAS reference 37">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=12197711" aria-label="PubMed reference 37">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 37" href="http://scholar.google.com/scholar_lookup?&title=Structures%20of%20the%20muraymycins%2C%20novel%20peptidoglycan%20biosynthesis%20inhibitors&journal=J.%20Am.%20Chem.%20Soc.&doi=10.1021%2Fja017748h&volume=124&pages=10260-10261&publication_year=2002&author=McDonald%2CLA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="38."><p class="c-article-references__text" id="ref-CR38">Spork, A. P. et al. Lead structures for new antibacterials: stereocontrolled synthesis of a bioactive muraymycin analogue. <i>Chemistry</i> <b>20</b>, 15292–15297 (2014).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/chem.201404775" data-track-item_id="10.1002/chem.201404775" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2Fchem.201404775" aria-label="Article reference 38" data-doi="10.1002/chem.201404775">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC2cXhvVyks73M" aria-label="CAS reference 38">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=25318977" aria-label="PubMed reference 38">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 38" href="http://scholar.google.com/scholar_lookup?&title=Lead%20structures%20for%20new%20antibacterials%3A%20stereocontrolled%20synthesis%20of%20a%20bioactive%20muraymycin%20analogue&journal=Chemistry&doi=10.1002%2Fchem.201404775&volume=20&pages=15292-15297&publication_year=2014&author=Spork%2CAP"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="39."><p class="c-article-references__text" id="ref-CR39">Spork, A. P., Koppermann, S., Schier Nee Wohnig, S., Linder, R. & Ducho, C. Analogues of muraymycin nucleoside antibiotics with epimeric uridine-derived core structures. <i>Molecules</i> <b>23</b>, 2868–2888 (2018).</p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="40."><p class="c-article-references__text" id="ref-CR40">Al-Dabbagh, B. et al. Active site mapping of MraY, a member of the polyprenyl-phosphate N-acetylhexosamine 1-phosphate transferase superfamily, catalyzing the first membrane step of peptidoglycan biosynthesis. <i>Biochemistry</i> <b>47</b>, 8919–8928 (2008).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1021/bi8006274" data-track-item_id="10.1021/bi8006274" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1021%2Fbi8006274" aria-label="Article reference 40" data-doi="10.1021/bi8006274">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD1cXptlaqur8%3D" aria-label="CAS reference 40">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=18672909" aria-label="PubMed reference 40">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 40" href="http://scholar.google.com/scholar_lookup?&title=Active%20site%20mapping%20of%20MraY%2C%20a%20member%20of%20the%20polyprenyl-phosphate%20N-acetylhexosamine%201-phosphate%20transferase%20superfamily%2C%20catalyzing%20the%20first%20membrane%20step%20of%20peptidoglycan%20biosynthesis&journal=Biochemistry&doi=10.1021%2Fbi8006274&volume=47&pages=8919-8928&publication_year=2008&author=Al-Dabbagh%2CB"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="41."><p class="c-article-references__text" id="ref-CR41">Howard, N. I. & Bugg, T. D. H. Synthesis and activity of 5′-Uridinyl dipeptide analogues mimicking the amino terminal peptide chain of nucleoside antibiotic mureidomycin A. <i>Bioorg. Med. Chem.</i> <b>11</b>, 3083–3099 (2003).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/S0968-0896(03)00270-0" data-track-item_id="10.1016/S0968-0896(03)00270-0" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2FS0968-0896%2803%2900270-0" aria-label="Article reference 41" data-doi="10.1016/S0968-0896(03)00270-0">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD3sXks1amt7w%3D" aria-label="CAS reference 41">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=12818671" aria-label="PubMed reference 41">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 41" href="http://scholar.google.com/scholar_lookup?&title=Synthesis%20and%20activity%20of%205%E2%80%B2-Uridinyl%20dipeptide%20analogues%20mimicking%20the%20amino%20terminal%20peptide%20chain%20of%20nucleoside%20antibiotic%20mureidomycin%20A&journal=Bioorg.%20Med.%20Chem.&doi=10.1016%2FS0968-0896%2803%2900270-0&volume=11&pages=3083-3099&publication_year=2003&author=Howard%2CNI&author=Bugg%2CTDH"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="42."><p class="c-article-references__text" id="ref-CR42">A Gentle, C., A. Harrison, S., Inukai, M. & D. H. Bugg, T. Structure–function studies on nucleoside antibiotic mureidomycin A: synthesis of 5′-functionalised uridine models. <i>J. Chem. Soc. Perkin Trans.</i> <b>1</b>, 1287–1294 (1999).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1039/a901287g" data-track-item_id="10.1039/a901287g" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1039%2Fa901287g" aria-label="Article reference 42" data-doi="10.1039/a901287g">Article</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 42" href="http://scholar.google.com/scholar_lookup?&title=Structure%E2%80%93function%20studies%20on%20nucleoside%20antibiotic%20mureidomycin%20A%3A%20synthesis%20of%205%E2%80%B2-functionalised%20uridine%20models&journal=J.%20Chem.%20Soc.%2C%20Perkin%20Trans.&doi=10.1039%2Fa901287g&volume=1&pages=1287-1294&publication_year=1999&author=A%20Gentle%2CC&author=A.%20Harrison%2CS&author=Inukai%2CM&author=D.%20H.%20Bugg%2CT"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="43."><p class="c-article-references__text" id="ref-CR43">Arkin, M. R., Tang, Y. & Wells, J. A. Small-molecule inhibitors of protein-protein interactions: progressing toward the reality. <i>Chem. Biol.</i> <b>21</b>, 1102–1114 (2014).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.chembiol.2014.09.001" data-track-item_id="10.1016/j.chembiol.2014.09.001" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.chembiol.2014.09.001" aria-label="Article reference 43" data-doi="10.1016/j.chembiol.2014.09.001">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC2cXhsFyrur7J" aria-label="CAS reference 43">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=25237857" aria-label="PubMed reference 43">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4179228" aria-label="PubMed Central reference 43">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 43" href="http://scholar.google.com/scholar_lookup?&title=Small-molecule%20inhibitors%20of%20protein-protein%20interactions%3A%20progressing%20toward%20the%20reality&journal=Chem.%20Biol.&doi=10.1016%2Fj.chembiol.2014.09.001&volume=21&pages=1102-1114&publication_year=2014&author=Arkin%2CMR&author=Tang%2CY&author=Wells%2CJA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="44."><p class="c-article-references__text" id="ref-CR44">Dini, C. et al. Synthesis of the nucleoside moiety of liposidomycins: elucidation of the pharmacophore of this family of MraY inhibitors. <i>Bioorg. Med. Chem. Lett.</i> <b>10</b>, 1839–1843 (2000).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/S0960-894X(00)00349-8" data-track-item_id="10.1016/S0960-894X(00)00349-8" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2FS0960-894X%2800%2900349-8" aria-label="Article reference 44" data-doi="10.1016/S0960-894X(00)00349-8">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD3cXls1Gru78%3D" aria-label="CAS reference 44">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=10969981" aria-label="PubMed reference 44">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 44" href="http://scholar.google.com/scholar_lookup?&title=Synthesis%20of%20the%20nucleoside%20moiety%20of%20liposidomycins%3A%20elucidation%20of%20the%20pharmacophore%20of%20this%20family%20of%20MraY%20inhibitors&journal=Bioorg.%20Med%20Chem.%20Lett.&doi=10.1016%2FS0960-894X%2800%2900349-8&volume=10&pages=1839-1843&publication_year=2000&author=Dini%2CC"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="45."><p class="c-article-references__text" id="ref-CR45">Nikonenko, B. V. et al. Activity of SQ641, a capuramycin analog, in a murine model of tuberculosis. <i>Antimicrob. Agents Chemother.</i> <b>53</b>, 3138–3139 (2009).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1128/AAC.00366-09" data-track-item_id="10.1128/AAC.00366-09" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1128%2FAAC.00366-09" aria-label="Article reference 45" data-doi="10.1128/AAC.00366-09">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD1MXotlajsb8%3D" aria-label="CAS reference 45">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=19414567" aria-label="PubMed reference 45">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2704676" aria-label="PubMed Central reference 45">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 45" href="http://scholar.google.com/scholar_lookup?&title=Activity%20of%20SQ641%2C%20a%20capuramycin%20analog%2C%20in%20a%20murine%20model%20of%20tuberculosis&journal=Antimicrob.%20Agents%20Chemother.&doi=10.1128%2FAAC.00366-09&volume=53&pages=3138-3139&publication_year=2009&author=Nikonenko%2CBV"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="46."><p class="c-article-references__text" id="ref-CR46">Nikonenko, B. et al. Therapeutic efficacy of SQ641-NE against Mycobacterium tuberculosis. <i>Antimicrob. Agents Chemother.</i> <b>58</b>, 587–589 (2014).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1128/AAC.01254-13" data-track-item_id="10.1128/AAC.01254-13" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1128%2FAAC.01254-13" aria-label="Article reference 46" data-doi="10.1128/AAC.01254-13">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=24145521" aria-label="PubMed reference 46">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3910727" aria-label="PubMed Central reference 46">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 46" href="http://scholar.google.com/scholar_lookup?&title=Therapeutic%20efficacy%20of%20SQ641-NE%20against%20Mycobacterium%20tuberculosis&journal=Antimicrob.%20Agents%20Chemother.&doi=10.1128%2FAAC.01254-13&volume=58&pages=587-589&publication_year=2014&author=Nikonenko%2CB"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="47."><p class="c-article-references__text" id="ref-CR47">Siricilla, S., Mitachi, K., Wan, B., Franzblau, S. G. & Kurosu, M. Discovery of a capuramycin analog that kills nonreplicating Mycobacterium tuberculosis and its synergistic effects with translocase I inhibitors. <i>J. Antibiot. (Tokyo)</i> <b>68</b>, 271–278 (2015).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/ja.2014.133" data-track-item_id="10.1038/ja.2014.133" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fja.2014.133" aria-label="Article reference 47" data-doi="10.1038/ja.2014.133">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC2MXnt1Whsbg%3D" aria-label="CAS reference 47">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 47" href="http://scholar.google.com/scholar_lookup?&title=Discovery%20of%20a%20capuramycin%20analog%20that%20kills%20nonreplicating%20Mycobacterium%20tuberculosis%20and%20its%20synergistic%20effects%20with%20translocase%20I%20inhibitors&journal=J.%20Antibiot.%20%28Tokyo%29&doi=10.1038%2Fja.2014.133&volume=68&pages=271-278&publication_year=2015&author=Siricilla%2CS&author=Mitachi%2CK&author=Wan%2CB&author=Franzblau%2CSG&author=Kurosu%2CM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="48."><p class="c-article-references__text" id="ref-CR48">Moore, J. H. 2nd et al. Treatment of Clostridium difficile infection using SQ641, a capuramycin analogue, increases post-treatment survival and improves clinical measures of disease in a murine model. <i>J. Antimicrob. Chemother.</i> <b>71</b>, 1300–1306 (2016).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1093/jac/dkv479" data-track-item_id="10.1093/jac/dkv479" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1093%2Fjac%2Fdkv479" aria-label="Article reference 48" data-doi="10.1093/jac/dkv479">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=26832756" aria-label="PubMed reference 48">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830414" aria-label="PubMed Central reference 48">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 48" href="http://scholar.google.com/scholar_lookup?&title=Treatment%20of%20Clostridium%20difficile%20infection%20using%20SQ641%2C%20a%20capuramycin%20analogue%2C%20increases%20post-treatment%20survival%20and%20improves%20clinical%20measures%20of%20disease%20in%20a%20murine%20model&journal=J.%20Antimicrob.%20Chemother.&doi=10.1093%2Fjac%2Fdkv479&volume=71&pages=1300-1306&publication_year=2016&author=Moore%2CJH"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="49."><p class="c-article-references__text" id="ref-CR49">Kimura, K. et al. New types of liposidomycins that inhibit bacterial peptidoglycan synthesis and are produced by Streptomyces. I. Producing organism and medium components. <i>J. Antibiot. (Tokyo)</i> <b>51</b>, 640–646 (1998).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.7164/antibiotics.51.640" data-track-item_id="10.7164/antibiotics.51.640" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.7164%2Fantibiotics.51.640" aria-label="Article reference 49" data-doi="10.7164/antibiotics.51.640">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DyaK1cXltVyhtbk%3D" aria-label="CAS reference 49">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 49" href="http://scholar.google.com/scholar_lookup?&title=New%20types%20of%20liposidomycins%20that%20inhibit%20bacterial%20peptidoglycan%20synthesis%20and%20are%20produced%20by%20Streptomyces.%20I.%20Producing%20organism%20and%20medium%20components&journal=J.%20Antibiot.%20%28Tokyo%29&doi=10.7164%2Fantibiotics.51.640&volume=51&pages=640-646&publication_year=1998&author=Kimura%2CK"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="50."><p class="c-article-references__text" id="ref-CR50">Kimura, K. et al. New types of liposidomycins that inhibit bacterial peptidoglycan synthesis and are produced by Streptomyces. II. Isolation and structure elucidation. <i>J. Antibiot. (Tokyo)</i> <b>51</b>, 647–654 (1998).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.7164/antibiotics.51.647" data-track-item_id="10.7164/antibiotics.51.647" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.7164%2Fantibiotics.51.647" aria-label="Article reference 50" data-doi="10.7164/antibiotics.51.647">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DyaK1cXltVyhtbY%3D" aria-label="CAS reference 50">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 50" href="http://scholar.google.com/scholar_lookup?&title=New%20types%20of%20liposidomycins%20that%20inhibit%20bacterial%20peptidoglycan%20synthesis%20and%20are%20produced%20by%20Streptomyces.%20II.%20Isolation%20and%20structure%20elucidation&journal=J.%20Antibiot.%20%28Tokyo%29&doi=10.7164%2Fantibiotics.51.647&volume=51&pages=647-654&publication_year=1998&author=Kimura%2CK"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="51."><p class="c-article-references__text" id="ref-CR51">Esumi, Y. et al. New types of liposidomycins produced by Streptomyces that inhibit bacterial peptidoglycan synthesis. Structure elucidation of fatty acid components by tandem mass spectrometry. <i>J. Antibiot. (Tokyo)</i> <b>52</b>, 281–287 (1999).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.7164/antibiotics.52.281" data-track-item_id="10.7164/antibiotics.52.281" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.7164%2Fantibiotics.52.281" aria-label="Article reference 51" data-doi="10.7164/antibiotics.52.281">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DyaK1MXitFClsb8%3D" aria-label="CAS reference 51">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 51" href="http://scholar.google.com/scholar_lookup?&title=New%20types%20of%20liposidomycins%20produced%20by%20Streptomyces%20that%20inhibit%20bacterial%20peptidoglycan%20synthesis.%20Structure%20elucidation%20of%20fatty%20acid%20components%20by%20tandem%20mass%20spectrometry&journal=J.%20Antibiot.%20%28Tokyo%29&doi=10.7164%2Fantibiotics.52.281&volume=52&pages=281-287&publication_year=1999&author=Esumi%2CY"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="52."><p class="c-article-references__text" id="ref-CR52">Kimura, K. et al. Selective inhibition of the bacterial peptidoglycan biosynthesis by the new types of liposidomycins. <i>J. Antibiot. (Tokyo)</i> <b>51</b>, 1099–1104 (1998).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.7164/antibiotics.51.1099" data-track-item_id="10.7164/antibiotics.51.1099" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.7164%2Fantibiotics.51.1099" aria-label="Article reference 52" data-doi="10.7164/antibiotics.51.1099">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DyaK1MXhvFKruw%3D%3D" aria-label="CAS reference 52">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 52" href="http://scholar.google.com/scholar_lookup?&title=Selective%20inhibition%20of%20the%20bacterial%20peptidoglycan%20biosynthesis%20by%20the%20new%20types%20of%20liposidomycins&journal=J.%20Antibiot.%20%28Tokyo%29&doi=10.7164%2Fantibiotics.51.1099&volume=51&pages=1099-1104&publication_year=1998&author=Kimura%2CK"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="53."><p class="c-article-references__text" id="ref-CR53">Kimura, K.-i & Bugg, T. D. H. Recent advances in antimicrobial nucleoside antibiotics targeting cell wall biosynthesis. <i>Nat. Prod. Rep.</i> <b>20</b>, 252–273 (2003).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1039/b202149h" data-track-item_id="10.1039/b202149h" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1039%2Fb202149h" aria-label="Article reference 53" data-doi="10.1039/b202149h">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD3sXjslCqtr4%3D" aria-label="CAS reference 53">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=12735700" aria-label="PubMed reference 53">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 53" href="http://scholar.google.com/scholar_lookup?&title=Recent%20advances%20in%20antimicrobial%20nucleoside%20antibiotics%20targeting%20cell%20wall%20biosynthesis&journal=Nat.%20Prod.%20Rep.&doi=10.1039%2Fb202149h&volume=20&pages=252-273&publication_year=2003&author=Kimura%2CK-i&author=Bugg%2CTDH"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="54."><p class="c-article-references__text" id="ref-CR54">Tanino, T. et al. Synthesis and biological evaluation of muraymycin analogues active against anti-drug-resistant bacteria. <i>ACS Med. Chem. Lett.</i> <b>1</b>, 258–262 (2010).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1021/ml100057z" data-track-item_id="10.1021/ml100057z" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1021%2Fml100057z" aria-label="Article reference 54" data-doi="10.1021/ml100057z">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC3cXmslKqs7s%3D" aria-label="CAS reference 54">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=24900205" aria-label="PubMed reference 54">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4007965" aria-label="PubMed Central reference 54">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 54" href="http://scholar.google.com/scholar_lookup?&title=Synthesis%20and%20biological%20evaluation%20of%20muraymycin%20analogues%20active%20against%20anti-drug-resistant%20bacteria&journal=ACS%20Med.%20Chem.%20Lett.&doi=10.1021%2Fml100057z&volume=1&pages=258-262&publication_year=2010&author=Tanino%2CT"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="55."><p class="c-article-references__text" id="ref-CR55">Kabsch, W. XDS. <i>Acta Crystallogr. D</i>. <i>Biol. Crystallogr.</i> <b>66</b>, 125–132 (2010).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1107/S0907444909047337" data-track-item_id="10.1107/S0907444909047337" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1107%2FS0907444909047337" aria-label="Article reference 55" data-doi="10.1107/S0907444909047337">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC3cXhs1SisLc%3D" aria-label="CAS reference 55">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 55" href="http://scholar.google.com/scholar_lookup?&title=Xds.%20Acta%20Crystallogr%20D&journal=Biol.%20Crystallogr&doi=10.1107%2FS0907444909047337&volume=66&pages=125-132&publication_year=2010&author=Kabsch%2CW"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="56."><p class="c-article-references__text" id="ref-CR56">Foadi, J. et al. Clustering procedures for the optimal selection of data sets from multiple crystals in macromolecular crystallography. <i>Acta Crystallogr. D. Biol. Crystallogr.</i> <b>69</b>, 1617–1632 (2013).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1107/S0907444913012274" data-track-item_id="10.1107/S0907444913012274" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1107%2FS0907444913012274" aria-label="Article reference 56" data-doi="10.1107/S0907444913012274">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC3sXhtFygsrfK" aria-label="CAS reference 56">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23897484" aria-label="PubMed reference 56">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3727331" aria-label="PubMed Central reference 56">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 56" href="http://scholar.google.com/scholar_lookup?&title=Clustering%20procedures%20for%20the%20optimal%20selection%20of%20data%20sets%20from%20multiple%20crystals%20in%20macromolecular%20crystallography&journal=Acta%20Crystallogr%20D.%20Biol.%20Crystallogr&doi=10.1107%2FS0907444913012274&volume=69&pages=1617-1632&publication_year=2013&author=Foadi%2CJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="57."><p class="c-article-references__text" id="ref-CR57">Tickle, I. J. et al. STARANISO. <i>Global Phasing, Inc</i>. (2019). <a href="http://staraniso.globalphasing.org/cgi-bin/staraniso.cgi" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="http://staraniso.globalphasing.org/cgi-bin/staraniso.cgi">http://staraniso.globalphasing.org/cgi-bin/staraniso.cgi</a>.</p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="58."><p class="c-article-references__text" id="ref-CR58">McCoy, A. J. et al. Phaser crystallographic software. <i>J. Appl. Crystallogr.</i> <b>40</b>, 658–674 (2007).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1107/S0021889807021206" data-track-item_id="10.1107/S0021889807021206" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1107%2FS0021889807021206" aria-label="Article reference 58" data-doi="10.1107/S0021889807021206">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD2sXnslWqsLk%3D" aria-label="CAS reference 58">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=19461840" aria-label="PubMed reference 58">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2483472" aria-label="PubMed Central reference 58">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 58" href="http://scholar.google.com/scholar_lookup?&title=Phaser%20crystallographic%20software&journal=J.%20Appl%20Crystallogr&doi=10.1107%2FS0021889807021206&volume=40&pages=658-674&publication_year=2007&author=McCoy%2CAJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="59."><p class="c-article-references__text" id="ref-CR59">Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. <i>Acta Crystallogr. D Biol. Crystallogr.</i> <b>66</b>, 486–501 (2010).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1107/S0907444910007493" data-track-item_id="10.1107/S0907444910007493" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1107%2FS0907444910007493" aria-label="Article reference 59" data-doi="10.1107/S0907444910007493">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC3cXksFKisb8%3D" aria-label="CAS reference 59">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=20383002" aria-label="PubMed reference 59">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2852313" aria-label="PubMed Central reference 59">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 59" href="http://scholar.google.com/scholar_lookup?&title=Features%20and%20development%20of%20Coot&journal=Acta%20Crystallogr.%20D%20Biol.%20Crystallogr.&doi=10.1107%2FS0907444910007493&volume=66&pages=486-501&publication_year=2010&author=Emsley%2CP&author=Lohkamp%2CB&author=Scott%2CWG&author=Cowtan%2CK"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="60."><p class="c-article-references__text" id="ref-CR60">Afonine, P. V. et al. Towards automated crystallographic structure refinement with phenix.refine. <i>Acta Crystallogr. D Biol. Crystallogr.</i> <b>68</b>, 352–367 (2012).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1107/S0907444912001308" data-track-item_id="10.1107/S0907444912001308" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1107%2FS0907444912001308" aria-label="Article reference 60" data-doi="10.1107/S0907444912001308">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC38Xlt1Ggu7c%3D" aria-label="CAS reference 60">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=22505256" aria-label="PubMed reference 60">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3322595" aria-label="PubMed Central reference 60">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 60" href="http://scholar.google.com/scholar_lookup?&title=Towards%20automated%20crystallographic%20structure%20refinement%20with%20phenix.refine&journal=Acta%20Crystallogr.%20D%20Biol.%20Crystallogr.&doi=10.1107%2FS0907444912001308&volume=68&pages=352-367&publication_year=2012&author=Afonine%2CPV"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="61."><p class="c-article-references__text" id="ref-CR61">Kovalevskiy, O., Nicholls, R. A. & Murshudov, G. N. Automated refinement of macromolecular structures at low resolution using prior information. <i>Acta Crystallogr. D Struct. Biol.</i> <b>72</b>, 1149–1161 (2016).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1107/S2059798316014534" data-track-item_id="10.1107/S2059798316014534" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1107%2FS2059798316014534" aria-label="Article reference 61" data-doi="10.1107/S2059798316014534">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC28Xhs1aktrvJ" aria-label="CAS reference 61">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=27710936" aria-label="PubMed reference 61">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053141" aria-label="PubMed Central reference 61">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 61" href="http://scholar.google.com/scholar_lookup?&title=Automated%20refinement%20of%20macromolecular%20structures%20at%20low%20resolution%20using%20prior%20information&journal=Acta%20Crystallogr.%20D%20Struct.%20Biol.&doi=10.1107%2FS2059798316014534&volume=72&pages=1149-1161&publication_year=2016&author=Kovalevskiy%2CO&author=Nicholls%2CRA&author=Murshudov%2CGN"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="62."><p class="c-article-references__text" id="ref-CR62">The PyMOL Molecular Graphics System. <i>Version 2.0 Schrödinger, LLC</i>.</p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="63."><p class="c-article-references__text" id="ref-CR63">Celniker, G. et al. ConSurf: using evolutionary data to raise testable hypotheses about protein function. <i>Isr. J. Chem.</i> <b>53</b>, 199–206 (2013).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/ijch.201200096" data-track-item_id="10.1002/ijch.201200096" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2Fijch.201200096" aria-label="Article reference 63" data-doi="10.1002/ijch.201200096">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC3sXlvFWlsLw%3D" aria-label="CAS reference 63">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 63" href="http://scholar.google.com/scholar_lookup?&title=ConSurf%3A%20using%20evolutionary%20data%20to%20raise%20testable%20hypotheses%20about%20protein%20function&journal=Isr.%20J.%20Chem.&doi=10.1002%2Fijch.201200096&volume=53&pages=199-206&publication_year=2013&author=Celniker%2CG"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="64."><p class="c-article-references__text" id="ref-CR64">Das, D., Walvoort, M. T., Lukose, V. & Imperiali, B. A rapid and efficient luminescence-based method for assaying phosphoglycosyltransferase enzymes. <i>Sci. Rep.</i> <b>6</b>, 33412 (2016).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/srep33412" data-track-item_id="10.1038/srep33412" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fsrep33412" aria-label="Article reference 64" data-doi="10.1038/srep33412">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="ads reference" data-track-action="ads reference" href="http://adsabs.harvard.edu/cgi-bin/nph-data_query?link_type=ABSTRACT&bibcode=2016NatSR...633412D" aria-label="ADS reference 64">ADS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC28XhsFamsL3M" aria-label="CAS reference 64">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=27624811" aria-label="PubMed reference 64">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5022061" aria-label="PubMed Central reference 64">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 64" href="http://scholar.google.com/scholar_lookup?&title=A%20rapid%20and%20efficient%20luminescence-based%20method%20for%20assaying%20phosphoglycosyltransferase%20enzymes&journal=Sci.%20Rep.&doi=10.1038%2Fsrep33412&volume=6&publication_year=2016&author=Das%2CD&author=Walvoort%2CMT&author=Lukose%2CV&author=Imperiali%2CB"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="65."><p class="c-article-references__text" id="ref-CR65">Kurosu, M., Li, K. & Crick, D. C. Concise synthesis of capuramycin. <i>Org. Lett.</i> <b>11</b>, 2393–2396 (2009).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1021/ol900458w" data-track-item_id="10.1021/ol900458w" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1021%2Fol900458w" aria-label="Article reference 65" data-doi="10.1021/ol900458w">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD1MXlt1ClsLc%3D" aria-label="CAS reference 65">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=19405507" aria-label="PubMed reference 65">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4784474" aria-label="PubMed Central reference 65">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 65" href="http://scholar.google.com/scholar_lookup?&title=Concise%20synthesis%20of%20capuramycin&journal=Org.%20Lett.&doi=10.1021%2Fol900458w&volume=11&pages=2393-2396&publication_year=2009&author=Kurosu%2CM&author=Li%2CK&author=Crick%2CDC"> Google Scholar</a> </p></li></ol><p class="c-article-references__download u-hide-print"><a data-track="click" data-track-action="download citation references" data-track-label="link" rel="nofollow" href="https://citation-needed.springer.com/v2/references/10.1038/s41467-019-10957-9?format=refman&flavour=references">Download references<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-download-medium"></use></svg></a></p></div></div></div></section></div><section data-title="Acknowledgements"><div class="c-article-section" id="Ack1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Ack1">Acknowledgements</h2><div class="c-article-section__content" id="Ack1-content"><p>Data for this study were collected at beamlines NECAT 24-ID-C and 24-ID-E and at SERCAT 22-ID, both at the Advanced Photon Source. We thank A. Kuk and N. Wright for help with data processing and model building and J. Yoo for help with initial nanobody screening. This work was supported by the National Institutes of Health (R01GM120594 to S.-Y.L.), JSPS Grant-in-Aid for Scientific Research (16H05097, 18H04599, and 19H03345 to S.I.), Astellas Foundation for Research on Metabolic Disorders (to S.I.), Hokkaido University GFC, PSOU, funded by MEXT (to S.I.), and BINDS from the Japan Agency for Medical Research and Development (to S.I.). Beamlines 24-ID-C and 24-ID-E are funded by P30 GM124165 and S10 RR029205.</p></div></div></section><section aria-labelledby="author-information" data-title="Author information"><div class="c-article-section" id="author-information-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="author-information">Author information</h2><div class="c-article-section__content" id="author-information-content"><h3 class="c-article__sub-heading" id="affiliations">Authors and Affiliations</h3><ol class="c-article-author-affiliation__list"><li id="Aff1"><p class="c-article-author-affiliation__address">Department of Biochemistry, Duke University Medical Center, 303 Research Drive, Durham, NC, 27710, USA</p><p class="c-article-author-affiliation__authors-list">Ellene H. Mashalidis, Benjamin Kaeser & Seok-Yong Lee</p></li><li id="Aff2"><p class="c-article-author-affiliation__address">Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nihi-6, Kita-ku, Sapporo, 060-0812, Japan</p><p class="c-article-author-affiliation__authors-list">Yuma Terasawa, Akira Katsuyama & Satoshi Ichikawa</p></li><li id="Aff3"><p class="c-article-author-affiliation__address">Department of Chemistry, Duke University, Durham, NC, 27708, USA</p><p class="c-article-author-affiliation__authors-list">Do-Yeon Kwon & Jiyong Hong</p></li><li id="Aff4"><p class="c-article-author-affiliation__address">Department of Chemistry, The Catholic University of Korea, Bucheon, 14662, Korea</p><p class="c-article-author-affiliation__authors-list">Kiyoun Lee</p></li></ol><div class="u-js-hide u-hide-print" data-test="author-info"><span class="c-article__sub-heading">Authors</span><ol class="c-article-authors-search u-list-reset"><li id="auth-Ellene_H_-Mashalidis-Aff1"><span class="c-article-authors-search__title u-h3 js-search-name">Ellene H. Mashalidis</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?author=Ellene%20H.%20Mashalidis" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Ellene%20H.%20Mashalidis" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Ellene%20H.%20Mashalidis%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li><li id="auth-Benjamin-Kaeser-Aff1"><span class="c-article-authors-search__title u-h3 js-search-name">Benjamin Kaeser</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?author=Benjamin%20Kaeser" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Benjamin%20Kaeser" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Benjamin%20Kaeser%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li><li id="auth-Yuma-Terasawa-Aff2"><span class="c-article-authors-search__title u-h3 js-search-name">Yuma Terasawa</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?author=Yuma%20Terasawa" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Yuma%20Terasawa" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Yuma%20Terasawa%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li><li id="auth-Akira-Katsuyama-Aff2"><span class="c-article-authors-search__title u-h3 js-search-name">Akira Katsuyama</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?author=Akira%20Katsuyama" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Akira%20Katsuyama" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Akira%20Katsuyama%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li><li id="auth-Do_Yeon-Kwon-Aff3"><span class="c-article-authors-search__title u-h3 js-search-name">Do-Yeon Kwon</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?author=Do-Yeon%20Kwon" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Do-Yeon%20Kwon" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Do-Yeon%20Kwon%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li><li id="auth-Kiyoun-Lee-Aff4"><span class="c-article-authors-search__title u-h3 js-search-name">Kiyoun Lee</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?author=Kiyoun%20Lee" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Kiyoun%20Lee" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Kiyoun%20Lee%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li><li id="auth-Jiyong-Hong-Aff3"><span class="c-article-authors-search__title u-h3 js-search-name">Jiyong Hong</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?author=Jiyong%20Hong" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Jiyong%20Hong" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Jiyong%20Hong%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li><li id="auth-Satoshi-Ichikawa-Aff2"><span class="c-article-authors-search__title u-h3 js-search-name">Satoshi Ichikawa</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?author=Satoshi%20Ichikawa" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Satoshi%20Ichikawa" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Satoshi%20Ichikawa%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li><li id="auth-Seok_Yong-Lee-Aff1"><span class="c-article-authors-search__title u-h3 js-search-name">Seok-Yong Lee</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?author=Seok-Yong%20Lee" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Seok-Yong%20Lee" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Seok-Yong%20Lee%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li></ol></div><h3 class="c-article__sub-heading" id="contributions">Contributions</h3><p>E.H.M. performed nanobody screening, MraY crystallization, data collection, model building, and enzyme assays; B.K. performed nanobody screening, MraY crystallization, and assisted in data collection and enzyme assay, all under the guidance of S.-Y.L. Y.T. and A.K. synthesized carbacaprazamycin and 3′-hydroxymureidomycin A under the guidance of S.I. D.-Y.K. and K.L. synthesized capuramycin under the guidance of J.H. E.H.M. and S.-Y.L. wrote the paper with input from the rest of the authors.</p><h3 class="c-article__sub-heading" id="corresponding-author">Corresponding author</h3><p id="corresponding-author-list">Correspondence to <a id="corresp-c1" href="mailto:seok-yong.lee@duke.edu">Seok-Yong Lee</a>.</p></div></div></section><section data-title="Ethics declarations"><div class="c-article-section" id="ethics-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="ethics">Ethics declarations</h2><div class="c-article-section__content" id="ethics-content"> <h3 class="c-article__sub-heading" id="FPar1">Competing interests</h3> <p>The authors declare no competing interests.</p> </div></div></section><section data-title="Additional information"><div class="c-article-section" id="additional-information-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="additional-information">Additional information</h2><div class="c-article-section__content" id="additional-information-content"><p><b>Peer review information:</b> <i>Nature Communications</i> thanks Yihua Huang and other anonymous reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.</p><p><b>Publisher’s note:</b> Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p></div></div></section><section data-title="Supplementary information"><div class="c-article-section" id="Sec21-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec21">Supplementary information</h2><div class="c-article-section__content" id="Sec21-content"><div data-test="supplementary-info"><div id="figshareContainer" class="c-article-figshare-container" data-test="figshare-container"></div><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM1"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="supplementary information" href="https://static-content.springer.com/esm/art%3A10.1038%2Fs41467-019-10957-9/MediaObjects/41467_2019_10957_MOESM1_ESM.pdf" data-supp-info-image="">Supplementary Information</a></h3></div><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM2"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="peer review file" href="https://static-content.springer.com/esm/art%3A10.1038%2Fs41467-019-10957-9/MediaObjects/41467_2019_10957_MOESM2_ESM.pdf" data-supp-info-image="">Peer Review File</a></h3></div><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM3"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="reporting summary" href="https://static-content.springer.com/esm/art%3A10.1038%2Fs41467-019-10957-9/MediaObjects/41467_2019_10957_MOESM3_ESM.pdf" data-supp-info-image="">Reporting Summary</a></h3></div></div></div></div></section><section data-title="Source data"><div class="c-article-section" id="Sec22-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec22">Source data</h2><div class="c-article-section__content" id="Sec22-content"><div data-test="supplementary-info"><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM4"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="source data" href="https://static-content.springer.com/esm/art%3A10.1038%2Fs41467-019-10957-9/MediaObjects/41467_2019_10957_MOESM4_ESM.xlsx" data-supp-info-image="">Source Data</a></h3></div></div></div></div></section><section data-title="Rights and permissions"><div class="c-article-section" id="rightslink-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="rightslink">Rights and permissions</h2><div class="c-article-section__content" id="rightslink-content"> <p><b>Open Access</b> This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit <a href="http://creativecommons.org/licenses/by/4.0/" rel="license">http://creativecommons.org/licenses/by/4.0/</a>.</p> <p class="c-article-rights"><a data-track="click" data-track-action="view rights and permissions" data-track-label="link" href="https://s100.copyright.com/AppDispatchServlet?title=Chemical%20logic%20of%20MraY%20inhibition%20by%20antibacterial%20nucleoside%20natural%20products&author=Ellene%20H.%20Mashalidis%20et%20al&contentID=10.1038%2Fs41467-019-10957-9&copyright=The%20Author%28s%29&publication=2041-1723&publicationDate=2019-07-02&publisherName=SpringerNature&orderBeanReset=true&oa=CC%20BY">Reprints and permissions</a></p></div></div></section><section aria-labelledby="article-info" data-title="About this article"><div class="c-article-section" id="article-info-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="article-info">About this article</h2><div class="c-article-section__content" id="article-info-content"><div class="c-bibliographic-information"><div class="u-hide-print c-bibliographic-information__column c-bibliographic-information__column--border"><a data-crossmark="10.1038/s41467-019-10957-9" target="_blank" rel="noopener" href="https://crossmark.crossref.org/dialog/?doi=10.1038/s41467-019-10957-9" data-track="click" data-track-action="Click Crossmark" data-track-label="link" data-test="crossmark"><img loading="lazy" width="57" height="81" alt="Check for updates. Verify currency and authenticity via CrossMark" src="data:image/svg+xml;base64,<svg height="81" width="57" xmlns="http://www.w3.org/2000/svg"><g fill="none" fill-rule="evenodd"><path d="m17.35 35.45 21.3-14.2v-17.03h-21.3" fill="#989898"/><path d="m38.65 35.45-21.3-14.2v-17.03h21.3" fill="#747474"/><path d="m28 .5c-12.98 0-23.5 10.52-23.5 23.5s10.52 23.5 23.5 23.5 23.5-10.52 23.5-23.5c0-6.23-2.48-12.21-6.88-16.62-4.41-4.4-10.39-6.88-16.62-6.88zm0 41.25c-9.8 0-17.75-7.95-17.75-17.75s7.95-17.75 17.75-17.75 17.75 7.95 17.75 17.75c0 4.71-1.87 9.22-5.2 12.55s-7.84 5.2-12.55 5.2z" fill="#535353"/><path d="m41 36c-5.81 6.23-15.23 7.45-22.43 2.9-7.21-4.55-10.16-13.57-7.03-21.5l-4.92-3.11c-4.95 10.7-1.19 23.42 8.78 29.71 9.97 6.3 23.07 4.22 30.6-4.86z" fill="#9c9c9c"/><path d="m.2 58.45c0-.75.11-1.42.33-2.01s.52-1.09.91-1.5c.38-.41.83-.73 1.34-.94.51-.22 1.06-.32 1.65-.32.56 0 1.06.11 1.51.35.44.23.81.5 1.1.81l-.91 1.01c-.24-.24-.49-.42-.75-.56-.27-.13-.58-.2-.93-.2-.39 0-.73.08-1.05.23-.31.16-.58.37-.81.66-.23.28-.41.63-.53 1.04-.13.41-.19.88-.19 1.39 0 1.04.23 1.86.68 2.46.45.59 1.06.88 1.84.88.41 0 .77-.07 1.07-.23s.59-.39.85-.68l.91 1c-.38.43-.8.76-1.28.99-.47.22-1 .34-1.58.34-.59 0-1.13-.1-1.64-.31-.5-.2-.94-.51-1.31-.91-.38-.4-.67-.9-.88-1.48-.22-.59-.33-1.26-.33-2.02zm8.4-5.33h1.61v2.54l-.05 1.33c.29-.27.61-.51.96-.72s.76-.31 1.24-.31c.73 0 1.27.23 1.61.71.33.47.5 1.14.5 2.02v4.31h-1.61v-4.1c0-.57-.08-.97-.25-1.21-.17-.23-.45-.35-.83-.35-.3 0-.56.08-.79.22-.23.15-.49.36-.78.64v4.8h-1.61zm7.37 6.45c0-.56.09-1.06.26-1.51.18-.45.42-.83.71-1.14.29-.3.63-.54 1.01-.71.39-.17.78-.25 1.18-.25.47 0 .88.08 1.23.24.36.16.65.38.89.67s.42.63.54 1.03c.12.41.18.84.18 1.32 0 .32-.02.57-.07.76h-4.36c.07.62.29 1.1.65 1.44.36.33.82.5 1.38.5.29 0 .57-.04.83-.13s.51-.21.76-.37l.55 1.01c-.33.21-.69.39-1.09.53-.41.14-.83.21-1.26.21-.48 0-.92-.08-1.34-.25-.41-.16-.76-.4-1.07-.7-.31-.31-.55-.69-.72-1.13-.18-.44-.26-.95-.26-1.52zm4.6-.62c0-.55-.11-.98-.34-1.28-.23-.31-.58-.47-1.06-.47-.41 0-.77.15-1.07.45-.31.29-.5.73-.58 1.3zm2.5.62c0-.57.09-1.08.28-1.53.18-.44.43-.82.75-1.13s.69-.54 1.1-.71c.42-.16.85-.24 1.31-.24.45 0 .84.08 1.17.23s.61.34.85.57l-.77 1.02c-.19-.16-.38-.28-.56-.37-.19-.09-.39-.14-.61-.14-.56 0-1.01.21-1.35.63-.35.41-.52.97-.52 1.67 0 .69.17 1.24.51 1.66.34.41.78.62 1.32.62.28 0 .54-.06.78-.17.24-.12.45-.26.64-.42l.67 1.03c-.33.29-.69.51-1.08.65-.39.15-.78.23-1.18.23-.46 0-.9-.08-1.31-.24-.4-.16-.75-.39-1.05-.7s-.53-.69-.7-1.13c-.17-.45-.25-.96-.25-1.53zm6.91-6.45h1.58v6.17h.05l2.54-3.16h1.77l-2.35 2.8 2.59 4.07h-1.75l-1.77-2.98-1.08 1.23v1.75h-1.58zm13.69 1.27c-.25-.11-.5-.17-.75-.17-.58 0-.87.39-.87 1.16v.75h1.34v1.27h-1.34v5.6h-1.61v-5.6h-.92v-1.2l.92-.07v-.72c0-.35.04-.68.13-.98.08-.31.21-.57.4-.79s.42-.39.71-.51c.28-.12.63-.18 1.04-.18.24 0 .48.02.69.07.22.05.41.1.57.17zm.48 5.18c0-.57.09-1.08.27-1.53.17-.44.41-.82.72-1.13.3-.31.65-.54 1.04-.71.39-.16.8-.24 1.23-.24s.84.08 1.24.24c.4.17.74.4 1.04.71s.54.69.72 1.13c.19.45.28.96.28 1.53s-.09 1.08-.28 1.53c-.18.44-.42.82-.72 1.13s-.64.54-1.04.7-.81.24-1.24.24-.84-.08-1.23-.24-.74-.39-1.04-.7c-.31-.31-.55-.69-.72-1.13-.18-.45-.27-.96-.27-1.53zm1.65 0c0 .69.14 1.24.43 1.66.28.41.68.62 1.18.62.51 0 .9-.21 1.19-.62.29-.42.44-.97.44-1.66 0-.7-.15-1.26-.44-1.67-.29-.42-.68-.63-1.19-.63-.5 0-.9.21-1.18.63-.29.41-.43.97-.43 1.67zm6.48-3.44h1.33l.12 1.21h.05c.24-.44.54-.79.88-1.02.35-.24.7-.36 1.07-.36.32 0 .59.05.78.14l-.28 1.4-.33-.09c-.11-.01-.23-.02-.38-.02-.27 0-.56.1-.86.31s-.55.58-.77 1.1v4.2h-1.61zm-47.87 15h1.61v4.1c0 .57.08.97.25 1.2.17.24.44.35.81.35.3 0 .57-.07.8-.22.22-.15.47-.39.73-.73v-4.7h1.61v6.87h-1.32l-.12-1.01h-.04c-.3.36-.63.64-.98.86-.35.21-.76.32-1.24.32-.73 0-1.27-.24-1.61-.71-.33-.47-.5-1.14-.5-2.02zm9.46 7.43v2.16h-1.61v-9.59h1.33l.12.72h.05c.29-.24.61-.45.97-.63.35-.17.72-.26 1.1-.26.43 0 .81.08 1.15.24.33.17.61.4.84.71.24.31.41.68.53 1.11.13.42.19.91.19 1.44 0 .59-.09 1.11-.25 1.57-.16.47-.38.85-.65 1.16-.27.32-.58.56-.94.73-.35.16-.72.25-1.1.25-.3 0-.6-.07-.9-.2s-.59-.31-.87-.56zm0-2.3c.26.22.5.37.73.45.24.09.46.13.66.13.46 0 .84-.2 1.15-.6.31-.39.46-.98.46-1.77 0-.69-.12-1.22-.35-1.61-.23-.38-.61-.57-1.13-.57-.49 0-.99.26-1.52.77zm5.87-1.69c0-.56.08-1.06.25-1.51.16-.45.37-.83.65-1.14.27-.3.58-.54.93-.71s.71-.25 1.08-.25c.39 0 .73.07 1 .2.27.14.54.32.81.55l-.06-1.1v-2.49h1.61v9.88h-1.33l-.11-.74h-.06c-.25.25-.54.46-.88.64-.33.18-.69.27-1.06.27-.87 0-1.56-.32-2.07-.95s-.76-1.51-.76-2.65zm1.67-.01c0 .74.13 1.31.4 1.7.26.38.65.58 1.15.58.51 0 .99-.26 1.44-.77v-3.21c-.24-.21-.48-.36-.7-.45-.23-.08-.46-.12-.7-.12-.45 0-.82.19-1.13.59-.31.39-.46.95-.46 1.68zm6.35 1.59c0-.73.32-1.3.97-1.71.64-.4 1.67-.68 3.08-.84 0-.17-.02-.34-.07-.51-.05-.16-.12-.3-.22-.43s-.22-.22-.38-.3c-.15-.06-.34-.1-.58-.1-.34 0-.68.07-1 .2s-.63.29-.93.47l-.59-1.08c.39-.24.81-.45 1.28-.63.47-.17.99-.26 1.54-.26.86 0 1.51.25 1.93.76s.63 1.25.63 2.21v4.07h-1.32l-.12-.76h-.05c-.3.27-.63.48-.98.66s-.73.27-1.14.27c-.61 0-1.1-.19-1.48-.56-.38-.36-.57-.85-.57-1.46zm1.57-.12c0 .3.09.53.27.67.19.14.42.21.71.21.28 0 .54-.07.77-.2s.48-.31.73-.56v-1.54c-.47.06-.86.13-1.18.23-.31.09-.57.19-.76.31s-.33.25-.41.4c-.09.15-.13.31-.13.48zm6.29-3.63h-.98v-1.2l1.06-.07.2-1.88h1.34v1.88h1.75v1.27h-1.75v3.28c0 .8.32 1.2.97 1.2.12 0 .24-.01.37-.04.12-.03.24-.07.34-.11l.28 1.19c-.19.06-.4.12-.64.17-.23.05-.49.08-.76.08-.4 0-.74-.06-1.02-.18-.27-.13-.49-.3-.67-.52-.17-.21-.3-.48-.37-.78-.08-.3-.12-.64-.12-1.01zm4.36 2.17c0-.56.09-1.06.27-1.51s.41-.83.71-1.14c.29-.3.63-.54 1.01-.71.39-.17.78-.25 1.18-.25.47 0 .88.08 1.23.24.36.16.65.38.89.67s.42.63.54 1.03c.12.41.18.84.18 1.32 0 .32-.02.57-.07.76h-4.37c.08.62.29 1.1.65 1.44.36.33.82.5 1.38.5.3 0 .58-.04.84-.13.25-.09.51-.21.76-.37l.54 1.01c-.32.21-.69.39-1.09.53s-.82.21-1.26.21c-.47 0-.92-.08-1.33-.25-.41-.16-.77-.4-1.08-.7-.3-.31-.54-.69-.72-1.13-.17-.44-.26-.95-.26-1.52zm4.61-.62c0-.55-.11-.98-.34-1.28-.23-.31-.58-.47-1.06-.47-.41 0-.77.15-1.08.45-.31.29-.5.73-.57 1.3zm3.01 2.23c.31.24.61.43.92.57.3.13.63.2.98.2.38 0 .65-.08.83-.23s.27-.35.27-.6c0-.14-.05-.26-.13-.37-.08-.1-.2-.2-.34-.28-.14-.09-.29-.16-.47-.23l-.53-.22c-.23-.09-.46-.18-.69-.3-.23-.11-.44-.24-.62-.4s-.33-.35-.45-.55c-.12-.21-.18-.46-.18-.75 0-.61.23-1.1.68-1.49.44-.38 1.06-.57 1.83-.57.48 0 .91.08 1.29.25s.71.36.99.57l-.74.98c-.24-.17-.49-.32-.73-.42-.25-.11-.51-.16-.78-.16-.35 0-.6.07-.76.21-.17.15-.25.33-.25.54 0 .14.04.26.12.36s.18.18.31.26c.14.07.29.14.46.21l.54.19c.23.09.47.18.7.29s.44.24.64.4c.19.16.34.35.46.58.11.23.17.5.17.82 0 .3-.06.58-.17.83-.12.26-.29.48-.51.68-.23.19-.51.34-.84.45-.34.11-.72.17-1.15.17-.48 0-.95-.09-1.41-.27-.46-.19-.86-.41-1.2-.68z" fill="#535353"/></g></svg>"></a></div><div class="c-bibliographic-information__column"><h3 class="c-article__sub-heading" id="citeas">Cite this article</h3><p class="c-bibliographic-information__citation">Mashalidis, E.H., Kaeser, B., Terasawa, Y. <i>et al.</i> Chemical logic of MraY inhibition by antibacterial nucleoside natural products. <i>Nat Commun</i> <b>10</b>, 2917 (2019). https://doi.org/10.1038/s41467-019-10957-9</p><p class="c-bibliographic-information__download-citation u-hide-print"><a data-test="citation-link" data-track="click" data-track-action="download article citation" data-track-label="link" data-track-external="" rel="nofollow" href="https://citation-needed.springer.com/v2/references/10.1038/s41467-019-10957-9?format=refman&flavour=citation">Download citation<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-download-medium"></use></svg></a></p><ul class="c-bibliographic-information__list" data-test="publication-history"><li class="c-bibliographic-information__list-item"><p>Received<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2019-03-20">20 March 2019</time></span></p></li><li class="c-bibliographic-information__list-item"><p>Accepted<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2019-06-06">06 June 2019</time></span></p></li><li class="c-bibliographic-information__list-item"><p>Published<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2019-07-02">02 July 2019</time></span></p></li><li class="c-bibliographic-information__list-item c-bibliographic-information__list-item--full-width"><p><abbr title="Digital Object Identifier">DOI</abbr><span class="u-hide">: </span><span class="c-bibliographic-information__value">https://doi.org/10.1038/s41467-019-10957-9</span></p></li></ul><div data-component="share-box"><div class="c-article-share-box u-display-none" hidden=""><h3 class="c-article__sub-heading">Share this article</h3><p class="c-article-share-box__description">Anyone you share the following link with will be able to read this content:</p><button class="js-get-share-url c-article-share-box__button" type="button" id="get-share-url" data-track="click" data-track-label="button" data-track-external="" data-track-action="get shareable link">Get shareable link</button><div class="js-no-share-url-container u-display-none" hidden=""><p class="js-c-article-share-box__no-sharelink-info c-article-share-box__no-sharelink-info">Sorry, a shareable link is not currently available for this article.</p></div><div class="js-share-url-container u-display-none" hidden=""><p class="js-share-url c-article-share-box__only-read-input" id="share-url" data-track="click" data-track-label="button" data-track-action="select share url"></p><button class="js-copy-share-url c-article-share-box__button--link-like" type="button" id="copy-share-url" data-track="click" data-track-label="button" data-track-action="copy share url" data-track-external="">Copy to clipboard</button></div><p class="js-c-article-share-box__additional-info c-article-share-box__additional-info"> Provided by the Springer Nature SharedIt content-sharing initiative </p></div></div><div data-component="article-info-list"></div></div></div></div></div></section> </div> <section> <div class="c-article-section js-article-section" id="further-reading-section" data-test="further-reading-section"> <h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="further-reading">This article is cited by</h2> <div class="c-article-section__content js-collapsible-section" id="further-reading-content"> <ul class="c-article-further-reading__list" id="further-reading-list"> <li class="c-article-further-reading__item js-ref-item"> <h3 class="c-article-further-reading__title" data-test="article-title"> <a class="print-link" data-track="click" data-track-action="view further reading article" data-track-label="link:Development of a natural product optimization strategy for inhibitors against MraY, a promising antibacterial target" href="https://doi.org/10.1038/s41467-024-49484-7"> Development of a natural product optimization strategy for inhibitors against MraY, a promising antibacterial target </a> </h3> <ul data-test="author-list" class="c-author-list c-author-list--compact c-author-list--truncated u-sans-serif u-mb-4 u-mt-auto"> <li>Kazuki Yamamoto</li><li>Toyotaka Sato</li><li>Satoshi Ichikawa</li> </ul> <p class="c-article-further-reading__journal-title"><i>Nature Communications</i> (2024)</p> </li> <li class="c-article-further-reading__item js-ref-item"> <h3 class="c-article-further-reading__title" data-test="article-title"> <a class="print-link" data-track="click" data-track-action="view further reading article" data-track-label="link:Unrealized targets in the discovery of antibiotics for Gram-negative bacterial infections" href="https://doi.org/10.1038/s41573-023-00791-6"> Unrealized targets in the discovery of antibiotics for Gram-negative bacterial infections </a> </h3> <ul data-test="author-list" class="c-author-list c-author-list--compact c-author-list--truncated u-sans-serif u-mb-4 u-mt-auto"> <li>Ursula Theuretzbacher</li><li>Benjamin Blasco</li><li>Laura J. V. Piddock</li> </ul> <p class="c-article-further-reading__journal-title"><i>Nature Reviews Drug Discovery</i> (2023)</p> </li> <li class="c-article-further-reading__item js-ref-item"> <h3 class="c-article-further-reading__title" data-test="article-title"> <a class="print-link" data-track="click" data-track-action="view further reading article" data-track-label="link:Peptidoglycan biosynthesis is driven by lipid transfer along enzyme-substrate affinity gradients" href="https://doi.org/10.1038/s41467-022-29836-x"> Peptidoglycan biosynthesis is driven by lipid transfer along enzyme-substrate affinity gradients </a> </h3> <ul data-test="author-list" class="c-author-list c-author-list--compact c-author-list--truncated u-sans-serif u-mb-4 u-mt-auto"> <li>Abraham O. Oluwole</li><li>Robin A. Corey</li><li>Carol V. Robinson</li> </ul> <p class="c-article-further-reading__journal-title"><i>Nature Communications</i> (2022)</p> </li> <li class="c-article-further-reading__item js-ref-item"> <h3 class="c-article-further-reading__title" data-test="article-title"> <a class="print-link" data-track="click" data-track-action="view further reading article" data-track-label="link:Synthesis of macrocyclic nucleoside antibacterials and their interactions with MraY" href="https://doi.org/10.1038/s41467-022-35227-z"> Synthesis of macrocyclic nucleoside antibacterials and their interactions with MraY </a> </h3> <ul data-test="author-list" class="c-author-list c-author-list--compact c-author-list--truncated u-sans-serif u-mb-4 u-mt-auto"> <li>Takeshi Nakaya</li><li>Miyuki Yabe</li><li>Satoshi Ichikawa</li> </ul> <p class="c-article-further-reading__journal-title"><i>Nature Communications</i> (2022)</p> </li> <li class="c-article-further-reading__item js-ref-item"> <h3 class="c-article-further-reading__title" data-test="article-title"> <a class="print-link" data-track="click" data-track-action="view further reading article" data-track-label="link:Molecular mechanism of mureidomycin biosynthesis activated by introduction of an exogenous regulatory gene ssaA into Streptomyces roseosporus" href="https://doi.org/10.1007/s11427-020-1892-3"> Molecular mechanism of mureidomycin biosynthesis activated by introduction of an exogenous regulatory gene ssaA into Streptomyces roseosporus </a> </h3> <ul data-test="author-list" class="c-author-list c-author-list--compact c-author-list--truncated u-sans-serif u-mb-4 u-mt-auto"> <li>Ning Liu</li><li>Hanye Guan</li><li>Huarong Tan</li> </ul> <p class="c-article-further-reading__journal-title"><i>Science China Life Sciences</i> (2021)</p> </li> </ul> </div> </div> </section> </div> </article> </main> <aside class="c-article-extras u-hide-print" aria-label="Article navigation" data-component-reading-companion data-container-type="reading-companion" data-track-component="reading companion"> <div class="js-context-bar-sticky-point-desktop" data-track-context="reading companion"> <div class="c-pdf-download u-clear-both js-pdf-download"> <a href="/articles/s41467-019-10957-9.pdf" class="u-button u-button--full-width u-button--primary u-justify-content-space-between c-pdf-download__link" data-article-pdf="true" data-readcube-pdf-url="true" data-test="download-pdf" data-draft-ignore="true" data-track="content_download" data-track-type="article pdf download" data-track-action="download pdf" data-track-label="link" data-track-external download> <span class="c-pdf-download__text">Download PDF</span> <svg aria-hidden="true" focusable="false" width="16" height="16" class="u-icon"><use xlink:href="#icon-download"/></svg> </a> </div> </div> <div class="c-reading-companion"> <div class="c-reading-companion__sticky" data-component="reading-companion-sticky" data-test="reading-companion-sticky"> <div class="c-reading-companion__panel c-reading-companion__sections c-reading-companion__panel--active" id="tabpanel-sections"> <div class="u-lazy-ad-wrapper u-mt-16 u-hide" data-component-mpu> <div class="c-ad c-ad--300x250"> <div class="c-ad__inner"> <p class="c-ad__label">Advertisement</p> <div id="div-gpt-ad-right-2" class="div-gpt-ad advert medium-rectangle js-ad text-center hide-print grade-c-hide" data-ad-type="right" data-test="right-ad" data-pa11y-ignore data-gpt data-gpt-unitpath="/285/nature_communications/article" data-gpt-sizes="300x250" data-gpt-targeting="type=article;pos=right;artid=s41467-019-10957-9;doi=10.1038/s41467-019-10957-9;techmeta=82,83;subjmeta=1172,1266,1290,22,326,45,535,607,631;kwrd=Antibiotics,Transferases,X-ray+crystallography"> <noscript> <a href="//pubads.g.doubleclick.net/gampad/jump?iu=/285/nature_communications/article&sz=300x250&c=1737100361&t=pos%3Dright%26type%3Darticle%26artid%3Ds41467-019-10957-9%26doi%3D10.1038/s41467-019-10957-9%26techmeta%3D82,83%26subjmeta%3D1172,1266,1290,22,326,45,535,607,631%26kwrd%3DAntibiotics,Transferases,X-ray+crystallography"> <img data-test="gpt-advert-fallback-img" src="//pubads.g.doubleclick.net/gampad/ad?iu=/285/nature_communications/article&sz=300x250&c=1737100361&t=pos%3Dright%26type%3Darticle%26artid%3Ds41467-019-10957-9%26doi%3D10.1038/s41467-019-10957-9%26techmeta%3D82,83%26subjmeta%3D1172,1266,1290,22,326,45,535,607,631%26kwrd%3DAntibiotics,Transferases,X-ray+crystallography" alt="Advertisement" width="300" height="250"></a> </noscript> </div> </div> </div> </div> </div> <div class="c-reading-companion__panel c-reading-companion__figures c-reading-companion__panel--full-width" id="tabpanel-figures"></div> <div class="c-reading-companion__panel c-reading-companion__references c-reading-companion__panel--full-width" id="tabpanel-references"></div> </div> </div> </aside> </div> <nav class="c-header__dropdown" aria-labelledby="Explore-content" data-test="Explore-content" id="explore" data-track-component="nature-150-split-header"> <div class="c-header__container"> <h2 id="Explore-content" class="c-header__heading c-header__heading--js-hide">Explore content</h2> <ul class="c-header__list c-header__list--js-stack"> <li class="c-header__item"> <a class="c-header__link" href="/ncomms/research-articles" data-track="click" data-track-action="research articles" data-track-label="link" data-test="explore-nav-item"> Research articles </a> </li> <li class="c-header__item"> <a class="c-header__link" href="/ncomms/reviews-and-analysis" data-track="click" data-track-action="reviews & analysis" data-track-label="link" data-test="explore-nav-item"> Reviews & Analysis </a> </li> <li class="c-header__item"> <a class="c-header__link" href="/ncomms/news-and-comment" data-track="click" data-track-action="news & comment" data-track-label="link" data-test="explore-nav-item"> News & Comment </a> </li> <li class="c-header__item"> <a class="c-header__link" href="/ncomms/video" data-track="click" data-track-action="videos" data-track-label="link" data-test="explore-nav-item"> Videos </a> </li> <li class="c-header__item"> <a class="c-header__link" href="/ncomms/collections" data-track="click" data-track-action="collections" data-track-label="link" data-test="explore-nav-item"> Collections </a> </li> <li class="c-header__item"> <a class="c-header__link" href="/ncomms/browse-subjects" data-track="click" data-track-action="subjects" data-track-label="link" data-test="explore-nav-item"> Subjects </a> </li> </ul> <ul class="c-header__list c-header__list--js-stack"> <li class="c-header__item"> <a class="c-header__link" href="https://www.facebook.com/NatureCommunications" data-track="click" data-track-action="facebook" data-track-label="link">Follow us on Facebook </a> </li> <li class="c-header__item"> <a class="c-header__link" href="https://twitter.com/NatureComms" data-track="click" data-track-action="twitter" data-track-label="link">Follow us on Twitter </a> </li> <li class="c-header__item c-header__item--hide-lg"> <a class="c-header__link" href="https://www.nature.com/my-account/alerts/subscribe-journal?list-id=264" rel="nofollow" data-track="click" data-track-action="Sign up for alerts" data-track-external data-track-label="link (mobile dropdown)">Sign up for alerts<svg role="img" aria-hidden="true" focusable="false" height="18" viewBox="0 0 18 18" width="18" xmlns="http://www.w3.org/2000/svg"><path d="m4 10h2.5c.27614237 0 .5.2238576.5.5s-.22385763.5-.5.5h-3.08578644l-1.12132034 1.1213203c-.18753638.1875364-.29289322.4418903-.29289322.7071068v.1715729h14v-.1715729c0-.2652165-.1053568-.5195704-.2928932-.7071068l-1.7071068-1.7071067v-3.4142136c0-2.76142375-2.2385763-5-5-5-2.76142375 0-5 2.23857625-5 5zm3 4c0 1.1045695.8954305 2 2 2s2-.8954305 2-2zm-5 0c-.55228475 0-1-.4477153-1-1v-.1715729c0-.530433.21071368-1.0391408.58578644-1.4142135l1.41421356-1.4142136v-3c0-3.3137085 2.6862915-6 6-6s6 2.6862915 6 6v3l1.4142136 1.4142136c.3750727.3750727.5857864.8837805.5857864 1.4142135v.1715729c0 .5522847-.4477153 1-1 1h-4c0 1.6568542-1.3431458 3-3 3-1.65685425 0-3-1.3431458-3-3z" fill="#fff"/></svg> </a> </li> <li class="c-header__item c-header__item--hide-lg"> <a class="c-header__link" href="https://www.nature.com/ncomms.rss" data-track="click" data-track-action="rss feed" data-track-label="link"> <span>RSS feed</span> </a> </li> </ul> </div> </nav> <nav class="c-header__dropdown" aria-labelledby="About-the-journal" id="about-the-journal" data-test="about-the-journal" data-track-component="nature-150-split-header"> <div class="c-header__container"> <h2 id="About-the-journal" class="c-header__heading c-header__heading--js-hide">About the journal</h2> <ul class="c-header__list c-header__list--js-stack"> <li class="c-header__item"> <a class="c-header__link" href="/ncomms/aims" data-track="click" data-track-action="aims & scope" data-track-label="link"> Aims & Scope </a> </li> <li class="c-header__item"> <a class="c-header__link" href="/ncomms/editors" data-track="click" data-track-action="editors" data-track-label="link"> Editors </a> </li> <li class="c-header__item"> <a class="c-header__link" href="/ncomms/journal-information" data-track="click" data-track-action="journal information" data-track-label="link"> Journal Information </a> </li> <li class="c-header__item"> <a class="c-header__link" href="/ncomms/open-access" data-track="click" data-track-action="open access fees and funding" data-track-label="link"> Open Access Fees and Funding </a> </li> <li class="c-header__item"> <a class="c-header__link" href="/ncomms/calls-for-papers" data-track="click" data-track-action="calls for papers" data-track-label="link"> Calls for Papers </a> </li> <li class="c-header__item"> <a class="c-header__link" href="/ncomms/editorial-values-statement" data-track="click" data-track-action="editorial values statement" data-track-label="link"> Editorial Values Statement </a> </li> <li class="c-header__item"> <a class="c-header__link" href="/ncomms/journal-impact" data-track="click" data-track-action="journal metrics" data-track-label="link"> Journal Metrics </a> </li> <li class="c-header__item"> <a class="c-header__link" href="/ncomms/editorshighlights" data-track="click" data-track-action="editors' highlights" data-track-label="link"> Editors' Highlights </a> </li> <li class="c-header__item"> <a class="c-header__link" href="/ncomms/contact" data-track="click" data-track-action="contact" data-track-label="link"> Contact </a> </li> <li class="c-header__item"> <a class="c-header__link" href="/ncomms/editorial-policies" data-track="click" data-track-action="editorial policies" data-track-label="link"> Editorial policies </a> </li> <li class="c-header__item"> <a class="c-header__link" href="/ncomms/top-articles" data-track="click" data-track-action="top articles" data-track-label="link"> Top Articles </a> </li> </ul> </div> </nav> <nav class="c-header__dropdown" aria-labelledby="Publish-with-us-label" id="publish-with-us" data-test="publish-with-us" data-track-component="nature-150-split-header"> <div class="c-header__container"> <h2 id="Publish-with-us-label" class="c-header__heading c-header__heading--js-hide">Publish with us</h2> <ul class="c-header__list c-header__list--js-stack"> <li class="c-header__item"> <a class="c-header__link" href="/ncomms/submit" data-track="click" data-track-action="for authors" data-track-label="link"> For authors </a> </li> <li class="c-header__item"> <a class="c-header__link" href="/ncomms/for-reviewers" data-track="click" data-track-action="for reviewers" data-track-label="link"> For Reviewers </a> </li> <li class="c-header__item"> <a class="c-header__link" data-test="nature-author-services" data-track="nav_language_services" data-track-context="header publish with us dropdown menu" data-track-action="manuscript author services" data-track-label="link manuscript author services" href="https://authorservices.springernature.com/go/sn/?utm_source=For+Authors&utm_medium=Website_Nature&utm_campaign=Platform+Experimentation+2022&utm_id=PE2022"> Language editing services </a> </li> <li class="c-header__item c-header__item--keyline"> <a class="c-header__link" href="https://mts-ncomms.nature.com/" data-track="click_submit_manuscript" data-track-context="submit link in Nature header dropdown menu" data-track-action="submit manuscript" data-track-label="link (publish with us dropdown menu)" data-track-external>Submit manuscript<svg role="img" aria-hidden="true" focusable="false" height="18" viewBox="0 0 18 18" width="18" xmlns="http://www.w3.org/2000/svg"><path d="m15 0c1.1045695 0 2 .8954305 2 2v5.5c0 .27614237-.2238576.5-.5.5s-.5-.22385763-.5-.5v-5.5c0-.51283584-.3860402-.93550716-.8833789-.99327227l-.1166211-.00672773h-9v3c0 1.1045695-.8954305 2-2 2h-3v10c0 .5128358.38604019.9355072.88337887.9932723l.11662113.0067277h7.5c.27614237 0 .5.2238576.5.5s-.22385763.5-.5.5h-7.5c-1.1045695 0-2-.8954305-2-2v-10.17157288c0-.53043297.21071368-1.0391408.58578644-1.41421356l3.82842712-3.82842712c.37507276-.37507276.88378059-.58578644 1.41421356-.58578644zm-.5442863 8.18867991 3.3545404 3.35454039c.2508994.2508994.2538696.6596433.0035959.909917-.2429543.2429542-.6561449.2462671-.9065387-.0089489l-2.2609825-2.3045251.0010427 7.2231989c0 .3569916-.2898381.6371378-.6473715.6371378-.3470771 0-.6473715-.2852563-.6473715-.6371378l-.0010428-7.2231995-2.2611222 2.3046654c-.2531661.2580415-.6562868.2592444-.9065605.0089707-.24295423-.2429542-.24865597-.6576651.0036132-.9099343l3.3546673-3.35466731c.2509089-.25090888.6612706-.25227691.9135302-.00001728zm-.9557137-3.18867991c.2761424 0 .5.22385763.5.5s-.2238576.5-.5.5h-6c-.27614237 0-.5-.22385763-.5-.5s.22385763-.5.5-.5zm-8.5-3.587-3.587 3.587h2.587c.55228475 0 1-.44771525 1-1zm8.5 1.587c.2761424 0 .5.22385763.5.5s-.2238576.5-.5.5h-6c-.27614237 0-.5-.22385763-.5-.5s.22385763-.5.5-.5z" fill="#fff"/></svg> </a> </li> </ul> </div> </nav> <div id="search-menu" class="c-header__dropdown c-header__dropdown--full-width" data-track-component="nature-150-split-header"> <div class="c-header__container"> <h2 class="c-header__visually-hidden">Search</h2> <form class="c-header__search-form" action="/search" method="get" role="search" autocomplete="off" data-test="inline-search"> <label class="c-header__heading" for="keywords">Search articles by subject, keyword or author</label> <div class="c-header__search-layout c-header__search-layout--max-width"> <div> <input type="text" required="" class="c-header__input" id="keywords" name="q" value=""> </div> <div class="c-header__search-layout"> <div> <label for="results-from" class="c-header__visually-hidden">Show results from</label> <select id="results-from" name="journal" class="c-header__select"> <option value="" selected>All journals</option> <option value="ncomms">This journal</option> </select> </div> <div> <button type="submit" class="c-header__search-button">Search</button> </div> </div> </div> </form> <div class="c-header__flush"> <a class="c-header__link" href="/search/advanced" data-track="click" data-track-action="advanced search" data-track-label="link"> Advanced search </a> </div> <h3 class="c-header__heading c-header__heading--keyline">Quick links</h3> <ul class="c-header__list"> <li><a class="c-header__link" href="/subjects" data-track="click" data-track-action="explore articles by subject" data-track-label="link">Explore articles by subject</a></li> <li><a class="c-header__link" href="/naturecareers" data-track="click" data-track-action="find a job" data-track-label="link">Find a job</a></li> <li><a class="c-header__link" href="/authors/index.html" data-track="click" data-track-action="guide to authors" data-track-label="link">Guide to authors</a></li> <li><a class="c-header__link" href="/authors/editorial_policies/" data-track="click" data-track-action="editorial policies" data-track-label="link">Editorial policies</a></li> </ul> </div> </div> <footer class="composite-layer" itemscope itemtype="http://schema.org/Periodical"> <meta itemprop="publisher" content="Springer Nature"> <div class="u-mt-16 u-mb-16"> <div class="u-container"> <div class="u-display-flex u-flex-wrap u-justify-content-space-between"> <p class="c-meta u-ma-0 u-flex-shrink"> <span class="c-meta__item"> Nature Communications (<i>Nat Commun</i>) </span> <span class="c-meta__item"> <abbr title="International Standard Serial Number">ISSN</abbr> <span itemprop="onlineIssn">2041-1723</span> (online) </span> </p> </div> </div> </div> <div class="c-footer"> <div class="u-hide-print" data-track-component="footer"> <h2 class="u-visually-hidden">nature.com sitemap</h2> <div class="c-footer__container"> <div class="c-footer__grid c-footer__group--separator"> <div class="c-footer__group"> <h3 class="c-footer__heading u-mt-0">About Nature Portfolio</h3> <ul class="c-footer__list"> <li class="c-footer__item"><a class="c-footer__link" href="https://www.nature.com/npg_/company_info/index.html" data-track="click" data-track-action="about us" data-track-label="link">About us</a></li> <li class="c-footer__item"><a class="c-footer__link" href="https://www.nature.com/npg_/press_room/press_releases.html" data-track="click" data-track-action="press releases" data-track-label="link">Press releases</a></li> <li class="c-footer__item"><a class="c-footer__link" href="https://press.nature.com/" data-track="click" data-track-action="press office" data-track-label="link">Press office</a></li> <li class="c-footer__item"><a class="c-footer__link" href="https://support.nature.com/support/home" data-track="click" data-track-action="contact us" data-track-label="link">Contact us</a></li> </ul> </div> <div class="c-footer__group"> <h3 class="c-footer__heading u-mt-0">Discover content</h3> <ul class="c-footer__list"> <li class="c-footer__item"><a class="c-footer__link" href="https://www.nature.com/siteindex" data-track="click" data-track-action="journals a-z" data-track-label="link">Journals A-Z</a></li> <li class="c-footer__item"><a class="c-footer__link" href="https://www.nature.com/subjects" data-track="click" data-track-action="article by subject" data-track-label="link">Articles by subject</a></li> <li class="c-footer__item"><a class="c-footer__link" href="https://www.protocols.io/" data-track="click" data-track-action="protocols.io" data-track-label="link">protocols.io</a></li> <li class="c-footer__item"><a class="c-footer__link" href="https://www.natureindex.com/" data-track="click" data-track-action="nature index" data-track-label="link">Nature Index</a></li> </ul> </div> <div class="c-footer__group"> <h3 class="c-footer__heading u-mt-0">Publishing policies</h3> <ul class="c-footer__list"> <li class="c-footer__item"><a class="c-footer__link" href="https://www.nature.com/authors/editorial_policies" data-track="click" data-track-action="Nature portfolio policies" data-track-label="link">Nature portfolio policies</a></li> <li class="c-footer__item"><a class="c-footer__link" href="https://www.nature.com/nature-research/open-access" data-track="click" data-track-action="open access" data-track-label="link">Open access</a></li> </ul> </div> <div class="c-footer__group"> <h3 class="c-footer__heading u-mt-0">Author & Researcher services</h3> <ul class="c-footer__list"> <li class="c-footer__item"><a class="c-footer__link" href="https://www.nature.com/reprints" data-track="click" data-track-action="reprints and permissions" data-track-label="link">Reprints & permissions</a></li> <li class="c-footer__item"><a class="c-footer__link" href="https://www.springernature.com/gp/authors/research-data" data-track="click" data-track-action="data research service" data-track-label="link">Research data</a></li> <li class="c-footer__item"><a class="c-footer__link" href="https://authorservices.springernature.com/language-editing/" data-track="click" data-track-action="language editing" data-track-label="link">Language editing</a></li> <li class="c-footer__item"><a class="c-footer__link" href="https://authorservices.springernature.com/scientific-editing/" data-track="click" data-track-action="scientific editing" data-track-label="link">Scientific editing</a></li> <li class="c-footer__item"><a class="c-footer__link" href="https://masterclasses.nature.com/" data-track="click" data-track-action="nature masterclasses" data-track-label="link">Nature Masterclasses</a></li> <li class="c-footer__item"><a class="c-footer__link" href="https://solutions.springernature.com/" data-track="click" data-track-action="research solutions" data-track-label="link">Research Solutions</a></li> </ul> </div> <div class="c-footer__group"> <h3 class="c-footer__heading u-mt-0">Libraries & institutions</h3> <ul class="c-footer__list"> <li class="c-footer__item"><a class="c-footer__link" href="https://www.springernature.com/gp/librarians/tools-services" data-track="click" data-track-action="librarian service and tools" data-track-label="link">Librarian service & tools</a></li> <li class="c-footer__item"><a class="c-footer__link" href="https://www.springernature.com/gp/librarians/manage-your-account/librarianportal" data-track="click" data-track-action="librarian portal" data-track-label="link">Librarian portal</a></li> <li class="c-footer__item"><a class="c-footer__link" href="https://www.nature.com/openresearch/about-open-access/information-for-institutions" data-track="click" data-track-action="open research" data-track-label="link">Open research</a></li> <li class="c-footer__item"><a class="c-footer__link" href="https://www.springernature.com/gp/librarians/recommend-to-your-library" data-track="click" data-track-action="Recommend to library" data-track-label="link">Recommend to library</a></li> </ul> </div> <div class="c-footer__group"> <h3 class="c-footer__heading u-mt-0">Advertising & partnerships</h3> <ul class="c-footer__list"> <li class="c-footer__item"><a class="c-footer__link" href="https://partnerships.nature.com/product/digital-advertising/" data-track="click" data-track-action="advertising" data-track-label="link">Advertising</a></li> <li class="c-footer__item"><a class="c-footer__link" href="https://partnerships.nature.com/" data-track="click" data-track-action="partnerships and services" data-track-label="link">Partnerships & Services</a></li> <li class="c-footer__item"><a class="c-footer__link" href="https://partnerships.nature.com/media-kits/" data-track="click" data-track-action="media kits" data-track-label="link">Media kits</a> </li> <li class="c-footer__item"><a class="c-footer__link" href="https://partnerships.nature.com/product/branded-content-native-advertising/" data-track-action="branded content" data-track-label="link">Branded content</a></li> </ul> </div> <div class="c-footer__group"> <h3 class="c-footer__heading u-mt-0">Professional development</h3> <ul class="c-footer__list"> <li class="c-footer__item"><a class="c-footer__link" href="https://www.nature.com/naturecareers/" data-track="click" data-track-action="nature careers" data-track-label="link">Nature Careers</a></li> <li class="c-footer__item"><a class="c-footer__link" href="https://conferences.nature.com" data-track="click" data-track-action="nature conferences" data-track-label="link">Nature<span class="u-visually-hidden"> </span> Conferences</a></li> </ul> </div> <div class="c-footer__group"> <h3 class="c-footer__heading u-mt-0">Regional websites</h3> <ul class="c-footer__list"> <li class="c-footer__item"><a class="c-footer__link" href="https://www.nature.com/natafrica" data-track="click" data-track-action="nature africa" data-track-label="link">Nature Africa</a></li> <li class="c-footer__item"><a class="c-footer__link" href="http://www.naturechina.com" data-track="click" data-track-action="nature china" data-track-label="link">Nature China</a></li> <li class="c-footer__item"><a class="c-footer__link" href="https://www.nature.com/nindia" data-track="click" data-track-action="nature india" data-track-label="link">Nature India</a></li> <li class="c-footer__item"><a class="c-footer__link" href="https://www.nature.com/natitaly" data-track="click" data-track-action="nature Italy" data-track-label="link">Nature Italy</a></li> <li class="c-footer__item"><a class="c-footer__link" href="https://www.natureasia.com/ja-jp" data-track="click" data-track-action="nature japan" data-track-label="link">Nature Japan</a></li> <li class="c-footer__item"><a class="c-footer__link" href="https://www.nature.com/nmiddleeast" data-track="click" data-track-action="nature middle east" data-track-label="link">Nature Middle East</a></li> </ul> </div> </div> </div> <div class="c-footer__container"> <ul class="c-footer__links"> <li class="c-footer__item"><a class="c-footer__link" href="https://www.nature.com/info/privacy" data-track="click" data-track-action="privacy policy" data-track-label="link">Privacy Policy</a></li> <li class="c-footer__item"><a class="c-footer__link" href="https://www.nature.com/info/cookies" data-track="click" data-track-action="use of cookies" data-track-label="link">Use of cookies</a></li> <li class="c-footer__item"> <button class="optanon-toggle-display c-footer__link" onclick="javascript:;" data-cc-action="preferences" data-track="click" data-track-action="manage cookies" data-track-label="link">Your privacy choices/Manage cookies </button> </li> <li class="c-footer__item"><a class="c-footer__link" href="https://www.nature.com/info/legal-notice" data-track="click" data-track-action="legal notice" data-track-label="link">Legal notice</a></li> <li class="c-footer__item"><a class="c-footer__link" href="https://www.nature.com/info/accessibility-statement" data-track="click" data-track-action="accessibility statement" data-track-label="link">Accessibility statement</a></li> <li class="c-footer__item"><a class="c-footer__link" href="https://www.nature.com/info/terms-and-conditions" data-track="click" data-track-action="terms and conditions" data-track-label="link">Terms & Conditions</a></li> <li class="c-footer__item"><a class="c-footer__link" href="https://www.springernature.com/ccpa" data-track="click" data-track-action="california privacy statement" data-track-label="link">Your US state privacy rights</a></li> </ul> </div> </div> <div class="c-footer__container"> <a href="https://www.springernature.com/" class="c-footer__link"> <img src="/static/images/logos/sn-logo-white-ea63208b81.svg" alt="Springer Nature" loading="lazy" width="200" height="20"/> </a> <p class="c-footer__legal" data-test="copyright">© 2024 Springer Nature Limited</p> </div> </div> <div class="u-visually-hidden" aria-hidden="true"> <?xml version="1.0" encoding="UTF-8"?><!DOCTYPE svg PUBLIC "-//W3C//DTD SVG 1.1//EN" "http://www.w3.org/Graphics/SVG/1.1/DTD/svg11.dtd"><svg xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink"><defs><path id="a" d="M0 .74h56.72v55.24H0z"/></defs><symbol id="icon-access" viewBox="0 0 18 18"><path d="m14 8c.5522847 0 1 .44771525 1 1v7h2.5c.2761424 0 .5.2238576.5.5v1.5h-18v-1.5c0-.2761424.22385763-.5.5-.5h2.5v-7c0-.55228475.44771525-1 1-1s1 .44771525 1 1v6.9996556h8v-6.9996556c0-.55228475.4477153-1 1-1zm-8 0 2 1v5l-2 1zm6 0v7l-2-1v-5zm-2.42653766-7.59857636 7.03554716 4.92488299c.4162533.29137735.5174853.86502537.226108 1.28127873-.1721584.24594054-.4534847.39241464-.7536934.39241464h-14.16284822c-.50810197 0-.92-.41189803-.92-.92 0-.30020869.1464741-.58153499.39241464-.75369337l7.03554714-4.92488299c.34432015-.2410241.80260453-.2410241 1.14692468 0zm-.57346234 2.03988748-3.65526982 2.55868888h7.31053962z" fill-rule="evenodd"/></symbol><symbol id="icon-account" viewBox="0 0 18 18"><path d="m10.2379028 16.9048051c1.3083556-.2032362 2.5118471-.7235183 3.5294683-1.4798399-.8731327-2.5141501-2.0638925-3.935978-3.7673711-4.3188248v-1.27684611c1.1651924-.41183641 2-1.52307546 2-2.82929429 0-1.65685425-1.3431458-3-3-3-1.65685425 0-3 1.34314575-3 3 0 1.30621883.83480763 2.41745788 2 2.82929429v1.27684611c-1.70347856.3828468-2.89423845 1.8046747-3.76737114 4.3188248 1.01762123.7563216 2.22111275 1.2766037 3.52946833 1.4798399.40563808.0629726.81921174.0951949 1.23790281.0951949s.83226473-.0322223 1.2379028-.0951949zm4.3421782-2.1721994c1.4927655-1.4532925 2.419919-3.484675 2.419919-5.7326057 0-4.418278-3.581722-8-8-8s-8 3.581722-8 8c0 2.2479307.92715352 4.2793132 2.41991895 5.7326057.75688473-2.0164459 1.83949951-3.6071894 3.48926591-4.3218837-1.14534283-.70360829-1.90918486-1.96796271-1.90918486-3.410722 0-2.209139 1.790861-4 4-4s4 1.790861 4 4c0 1.44275929-.763842 2.70711371-1.9091849 3.410722 1.6497664.7146943 2.7323812 2.3054378 3.4892659 4.3218837zm-5.580081 3.2673943c-4.97056275 0-9-4.0294373-9-9 0-4.97056275 4.02943725-9 9-9 4.9705627 0 9 4.02943725 9 9 0 4.9705627-4.0294373 9-9 9z" fill-rule="evenodd"/></symbol><symbol id="icon-alert" viewBox="0 0 18 18"><path d="m4 10h2.5c.27614237 0 .5.2238576.5.5s-.22385763.5-.5.5h-3.08578644l-1.12132034 1.1213203c-.18753638.1875364-.29289322.4418903-.29289322.7071068v.1715729h14v-.1715729c0-.2652165-.1053568-.5195704-.2928932-.7071068l-1.7071068-1.7071067v-3.4142136c0-2.76142375-2.2385763-5-5-5-2.76142375 0-5 2.23857625-5 5zm3 4c0 1.1045695.8954305 2 2 2s2-.8954305 2-2zm-5 0c-.55228475 0-1-.4477153-1-1v-.1715729c0-.530433.21071368-1.0391408.58578644-1.4142135l1.41421356-1.4142136v-3c0-3.3137085 2.6862915-6 6-6s6 2.6862915 6 6v3l1.4142136 1.4142136c.3750727.3750727.5857864.8837805.5857864 1.4142135v.1715729c0 .5522847-.4477153 1-1 1h-4c0 1.6568542-1.3431458 3-3 3-1.65685425 0-3-1.3431458-3-3z" fill-rule="evenodd"/></symbol><symbol id="icon-arrow-broad" viewBox="0 0 16 16"><path d="m6.10307866 2.97190702v7.69043288l2.44965196-2.44676915c.38776071-.38730439 1.0088052-.39493524 1.38498697-.01919617.38609051.38563612.38643641 1.01053024-.00013864 1.39665039l-4.12239817 4.11754683c-.38616704.3857126-1.01187344.3861062-1.39846576-.0000311l-4.12258206-4.11773056c-.38618426-.38572979-.39254614-1.00476697-.01636437-1.38050605.38609047-.38563611 1.01018509-.38751562 1.4012233.00306241l2.44985644 2.4469734v-8.67638639c0-.54139983.43698413-.98042709.98493125-.98159081l7.89910522-.0043627c.5451687 0 .9871152.44142642.9871152.98595351s-.4419465.98595351-.9871152.98595351z" fill-rule="evenodd" transform="matrix(-1 0 0 -1 14 15)"/></symbol><symbol id="icon-arrow-down" viewBox="0 0 16 16"><path d="m3.28337502 11.5302405 4.03074001 4.176208c.37758093.3912076.98937525.3916069 1.367372-.0000316l4.03091977-4.1763942c.3775978-.3912252.3838182-1.0190815.0160006-1.4001736-.3775061-.39113013-.9877245-.39303641-1.3700683.003106l-2.39538585 2.4818345v-11.6147896l-.00649339-.11662112c-.055753-.49733869-.46370161-.88337888-.95867408-.88337888-.49497246 0-.90292107.38604019-.95867408.88337888l-.00649338.11662112v11.6147896l-2.39518594-2.4816273c-.37913917-.39282218-.98637524-.40056175-1.35419292-.0194697-.37750607.3911302-.37784433 1.0249269.00013556 1.4165479z" fill-rule="evenodd"/></symbol><symbol id="icon-arrow-left" viewBox="0 0 16 16"><path d="m4.46975946 3.28337502-4.17620792 4.03074001c-.39120768.37758093-.39160691.98937525.0000316 1.367372l4.1763942 4.03091977c.39122514.3775978 1.01908149.3838182 1.40017357.0160006.39113012-.3775061.3930364-.9877245-.00310603-1.3700683l-2.48183446-2.39538585h11.61478958l.1166211-.00649339c.4973387-.055753.8833789-.46370161.8833789-.95867408 0-.49497246-.3860402-.90292107-.8833789-.95867408l-.1166211-.00649338h-11.61478958l2.4816273-2.39518594c.39282216-.37913917.40056173-.98637524.01946965-1.35419292-.39113012-.37750607-1.02492687-.37784433-1.41654791.00013556z" fill-rule="evenodd"/></symbol><symbol id="icon-arrow-right" viewBox="0 0 16 16"><path d="m11.5302405 12.716625 4.176208-4.03074003c.3912076-.37758093.3916069-.98937525-.0000316-1.367372l-4.1763942-4.03091981c-.3912252-.37759778-1.0190815-.38381821-1.4001736-.01600053-.39113013.37750607-.39303641.98772445.003106 1.37006824l2.4818345 2.39538588h-11.6147896l-.11662112.00649339c-.49733869.055753-.88337888.46370161-.88337888.95867408 0 .49497246.38604019.90292107.88337888.95867408l.11662112.00649338h11.6147896l-2.4816273 2.39518592c-.39282218.3791392-.40056175.9863753-.0194697 1.3541929.3911302.3775061 1.0249269.3778444 1.4165479-.0001355z" fill-rule="evenodd"/></symbol><symbol id="icon-arrow-sub" viewBox="0 0 16 16"><path d="m7.89692134 4.97190702v7.69043288l-2.44965196-2.4467692c-.38776071-.38730434-1.0088052-.39493519-1.38498697-.0191961-.38609047.3856361-.38643643 1.0105302.00013864 1.3966504l4.12239817 4.1175468c.38616704.3857126 1.01187344.3861062 1.39846576-.0000311l4.12258202-4.1177306c.3861843-.3857298.3925462-1.0047669.0163644-1.380506-.3860905-.38563612-1.0101851-.38751563-1.4012233.0030624l-2.44985643 2.4469734v-8.67638639c0-.54139983-.43698413-.98042709-.98493125-.98159081l-7.89910525-.0043627c-.54516866 0-.98711517.44142642-.98711517.98595351s.44194651.98595351.98711517.98595351z" fill-rule="evenodd"/></symbol><symbol id="icon-arrow-up" viewBox="0 0 16 16"><path d="m12.716625 4.46975946-4.03074003-4.17620792c-.37758093-.39120768-.98937525-.39160691-1.367372.0000316l-4.03091981 4.1763942c-.37759778.39122514-.38381821 1.01908149-.01600053 1.40017357.37750607.39113012.98772445.3930364 1.37006824-.00310603l2.39538588-2.48183446v11.61478958l.00649339.1166211c.055753.4973387.46370161.8833789.95867408.8833789.49497246 0 .90292107-.3860402.95867408-.8833789l.00649338-.1166211v-11.61478958l2.39518592 2.4816273c.3791392.39282216.9863753.40056173 1.3541929.01946965.3775061-.39113012.3778444-1.02492687-.0001355-1.41654791z" fill-rule="evenodd"/></symbol><symbol id="icon-article" viewBox="0 0 18 18"><path d="m13 15v-12.9906311c0-.0073595-.0019884-.0093689.0014977-.0093689l-11.00158888.00087166v13.00506804c0 .5482678.44615281.9940603.99415146.9940603h10.27350412c-.1701701-.2941734-.2675644-.6357129-.2675644-1zm-12 .0059397v-13.00506804c0-.5562408.44704472-1.00087166.99850233-1.00087166h11.00299537c.5510129 0 .9985023.45190985.9985023 1.0093689v2.9906311h3v9.9914698c0 1.1065798-.8927712 2.0085302-1.9940603 2.0085302h-12.01187942c-1.09954652 0-1.99406028-.8927712-1.99406028-1.9940603zm13-9.0059397v9c0 .5522847.4477153 1 1 1s1-.4477153 1-1v-9zm-10-2h7v4h-7zm1 1v2h5v-2zm-1 4h7v1h-7zm0 2h7v1h-7zm0 2h7v1h-7z" fill-rule="evenodd"/></symbol><symbol id="icon-audio" viewBox="0 0 18 18"><path d="m13.0957477 13.5588459c-.195279.1937043-.5119137.193729-.7072234.0000551-.1953098-.193674-.1953346-.5077061-.0000556-.7014104 1.0251004-1.0168342 1.6108711-2.3905226 1.6108711-3.85745208 0-1.46604976-.5850634-2.83898246-1.6090736-3.85566829-.1951894-.19379323-.1950192-.50782531.0003802-.70141028.1953993-.19358497.512034-.19341614.7072234.00037709 1.2094886 1.20083761 1.901635 2.8250555 1.901635 4.55670148 0 1.73268608-.6929822 3.35779608-1.9037571 4.55880738zm2.1233994 2.1025159c-.195234.193749-.5118687.1938462-.7072235.0002171-.1953548-.1936292-.1954528-.5076613-.0002189-.7014104 1.5832215-1.5711805 2.4881302-3.6939808 2.4881302-5.96012998 0-2.26581266-.9046382-4.3883241-2.487443-5.95944795-.1952117-.19377107-.1950777-.50780316.0002993-.70141031s.5120117-.19347426.7072234.00029682c1.7683321 1.75528196 2.7800854 4.12911258 2.7800854 6.66056144 0 2.53182498-1.0120556 4.90597838-2.7808529 6.66132328zm-14.21898205-3.6854911c-.5523759 0-1.00016505-.4441085-1.00016505-.991944v-3.96777631c0-.54783558.44778915-.99194407 1.00016505-.99194407h2.0003301l5.41965617-3.8393633c.44948677-.31842296 1.07413994-.21516983 1.39520191.23062232.12116339.16823446.18629727.36981184.18629727.57655577v12.01603479c0 .5478356-.44778914.9919441-1.00016505.9919441-.20845738 0-.41170538-.0645985-.58133413-.184766l-5.41965617-3.8393633zm0-.991944h2.32084805l5.68047235 4.0241292v-12.01603479l-5.68047235 4.02412928h-2.32084805z" fill-rule="evenodd"/></symbol><symbol id="icon-block" viewBox="0 0 24 24"><path d="m0 0h24v24h-24z" fill-rule="evenodd"/></symbol><symbol id="icon-book" viewBox="0 0 18 18"><path d="m4 13v-11h1v11h11v-11h-13c-.55228475 0-1 .44771525-1 1v10.2675644c.29417337-.1701701.63571286-.2675644 1-.2675644zm12 1h-13c-.55228475 0-1 .4477153-1 1s.44771525 1 1 1h13zm0 3h-13c-1.1045695 0-2-.8954305-2-2v-12c0-1.1045695.8954305-2 2-2h13c.5522847 0 1 .44771525 1 1v14c0 .5522847-.4477153 1-1 1zm-8.5-13h6c.2761424 0 .5.22385763.5.5s-.2238576.5-.5.5h-6c-.27614237 0-.5-.22385763-.5-.5s.22385763-.5.5-.5zm1 2h4c.2761424 0 .5.22385763.5.5s-.2238576.5-.5.5h-4c-.27614237 0-.5-.22385763-.5-.5s.22385763-.5.5-.5z" fill-rule="evenodd"/></symbol><symbol id="icon-broad" viewBox="0 0 24 24"><path d="m9.18274226 7.81v7.7999954l2.48162734-2.4816273c.3928221-.3928221 1.0219731-.4005617 1.4030652-.0194696.3911301.3911301.3914806 1.0249268-.0001404 1.4165479l-4.17620796 4.1762079c-.39120769.3912077-1.02508144.3916069-1.41671995-.0000316l-4.1763942-4.1763942c-.39122514-.3912251-.39767006-1.0190815-.01657798-1.4001736.39113012-.3911301 1.02337106-.3930364 1.41951349.0031061l2.48183446 2.4818344v-8.7999954c0-.54911294.4426881-.99439484.99778758-.99557515l8.00221246-.00442485c.5522847 0 1 .44771525 1 1s-.4477153 1-1 1z" fill-rule="evenodd" transform="matrix(-1 0 0 -1 20.182742 24.805206)"/></symbol><symbol id="icon-calendar" viewBox="0 0 18 18"><path d="m12.5 0c.2761424 0 .5.21505737.5.49047852v.50952148h2c1.1072288 0 2 .89451376 2 2v12c0 1.1072288-.8945138 2-2 2h-12c-1.1072288 0-2-.8945138-2-2v-12c0-1.1072288.89451376-2 2-2h1v1h-1c-.55393837 0-1 .44579254-1 1v3h14v-3c0-.55393837-.4457925-1-1-1h-2v1.50952148c0 .27088381-.2319336.49047852-.5.49047852-.2761424 0-.5-.21505737-.5-.49047852v-3.01904296c0-.27088381.2319336-.49047852.5-.49047852zm3.5 7h-14v8c0 .5539384.44579254 1 1 1h12c.5539384 0 1-.4457925 1-1zm-11 6v1h-1v-1zm3 0v1h-1v-1zm3 0v1h-1v-1zm-6-2v1h-1v-1zm3 0v1h-1v-1zm6 0v1h-1v-1zm-3 0v1h-1v-1zm-3-2v1h-1v-1zm6 0v1h-1v-1zm-3 0v1h-1v-1zm-5.5-9c.27614237 0 .5.21505737.5.49047852v.50952148h5v1h-5v1.50952148c0 .27088381-.23193359.49047852-.5.49047852-.27614237 0-.5-.21505737-.5-.49047852v-3.01904296c0-.27088381.23193359-.49047852.5-.49047852z" fill-rule="evenodd"/></symbol><symbol id="icon-cart" viewBox="0 0 18 18"><path d="m5 14c1.1045695 0 2 .8954305 2 2s-.8954305 2-2 2-2-.8954305-2-2 .8954305-2 2-2zm10 0c1.1045695 0 2 .8954305 2 2s-.8954305 2-2 2-2-.8954305-2-2 .8954305-2 2-2zm-10 1c-.55228475 0-1 .4477153-1 1s.44771525 1 1 1 1-.4477153 1-1-.44771525-1-1-1zm10 0c-.5522847 0-1 .4477153-1 1s.4477153 1 1 1 1-.4477153 1-1-.4477153-1-1-1zm-12.82032249-15c.47691417 0 .88746157.33678127.98070211.80449199l.23823144 1.19501025 13.36277974.00045554c.5522847.00001882.9999659.44774934.9999659 1.00004222 0 .07084994-.0075361.14150708-.022474.2107727l-1.2908094 5.98534344c-.1007861.46742419-.5432548.80388386-1.0571651.80388386h-10.24805106c-.59173366 0-1.07142857.4477153-1.07142857 1 0 .5128358.41361449.9355072.94647737.9932723l.1249512.0067277h10.35933776c.2749512 0 .4979349.2228539.4979349.4978051 0 .2749417-.2227336.4978951-.4976753.4980063l-10.35959736.0041886c-1.18346732 0-2.14285714-.8954305-2.14285714-2 0-.6625717.34520317-1.24989198.87690425-1.61383592l-1.63768102-8.19004794c-.01312273-.06561364-.01950005-.131011-.0196107-.19547395l-1.71961253-.00064219c-.27614237 0-.5-.22385762-.5-.5 0-.27614237.22385763-.5.5-.5zm14.53193359 2.99950224h-13.11300004l1.20580469 6.02530174c.11024034-.0163252.22327998-.02480398.33844139-.02480398h10.27064786z"/></symbol><symbol id="icon-chevron-less" viewBox="0 0 10 10"><path d="m5.58578644 4-3.29289322-3.29289322c-.39052429-.39052429-.39052429-1.02368927 0-1.41421356s1.02368927-.39052429 1.41421356 0l4 4c.39052429.39052429.39052429 1.02368927 0 1.41421356l-4 4c-.39052429.39052429-1.02368927.39052429-1.41421356 0s-.39052429-1.02368927 0-1.41421356z" fill-rule="evenodd" transform="matrix(0 -1 -1 0 9 9)"/></symbol><symbol id="icon-chevron-more" viewBox="0 0 10 10"><path d="m5.58578644 6-3.29289322-3.29289322c-.39052429-.39052429-.39052429-1.02368927 0-1.41421356s1.02368927-.39052429 1.41421356 0l4 4c.39052429.39052429.39052429 1.02368927 0 1.41421356l-4 4.00000002c-.39052429.3905243-1.02368927.3905243-1.41421356 0s-.39052429-1.02368929 0-1.41421358z" fill-rule="evenodd" transform="matrix(0 1 -1 0 11 1)"/></symbol><symbol id="icon-chevron-right" viewBox="0 0 10 10"><path d="m5.96738168 4.70639573 2.39518594-2.41447274c.37913917-.38219212.98637524-.38972225 1.35419292-.01894278.37750606.38054586.37784436.99719163-.00013556 1.37821513l-4.03074001 4.06319683c-.37758093.38062133-.98937525.38100976-1.367372-.00003075l-4.03091981-4.06337806c-.37759778-.38063832-.38381821-.99150444-.01600053-1.3622839.37750607-.38054587.98772445-.38240057 1.37006824.00302197l2.39538588 2.4146743.96295325.98624457z" fill-rule="evenodd" transform="matrix(0 -1 1 0 0 10)"/></symbol><symbol id="icon-circle-fill" viewBox="0 0 16 16"><path d="m8 14c-3.3137085 0-6-2.6862915-6-6s2.6862915-6 6-6 6 2.6862915 6 6-2.6862915 6-6 6z" fill-rule="evenodd"/></symbol><symbol id="icon-circle" viewBox="0 0 16 16"><path d="m8 12c2.209139 0 4-1.790861 4-4s-1.790861-4-4-4-4 1.790861-4 4 1.790861 4 4 4zm0 2c-3.3137085 0-6-2.6862915-6-6s2.6862915-6 6-6 6 2.6862915 6 6-2.6862915 6-6 6z" fill-rule="evenodd"/></symbol><symbol id="icon-citation" viewBox="0 0 18 18"><path d="m8.63593473 5.99995183c2.20913897 0 3.99999997 1.79084375 3.99999997 3.99996146 0 1.40730761-.7267788 2.64486871-1.8254829 3.35783281 1.6240224.6764218 2.8754442 2.0093871 3.4610603 3.6412466l-1.0763845.000006c-.5310008-1.2078237-1.5108121-2.1940153-2.7691712-2.7181346l-.79002167-.329052v-1.023992l.63016577-.4089232c.8482885-.5504661 1.3698342-1.4895187 1.3698342-2.51898361 0-1.65683828-1.3431457-2.99996146-2.99999997-2.99996146-1.65685425 0-3 1.34312318-3 2.99996146 0 1.02946491.52154569 1.96851751 1.36983419 2.51898361l.63016581.4089232v1.023992l-.79002171.329052c-1.25835905.5241193-2.23817037 1.5103109-2.76917113 2.7181346l-1.07638453-.000006c.58561612-1.6318595 1.8370379-2.9648248 3.46106024-3.6412466-1.09870405-.7129641-1.82548287-1.9505252-1.82548287-3.35783281 0-2.20911771 1.790861-3.99996146 4-3.99996146zm7.36897597-4.99995183c1.1018574 0 1.9950893.89353404 1.9950893 2.00274083v5.994422c0 1.10608317-.8926228 2.00274087-1.9950893 2.00274087l-3.0049107-.0009037v-1l3.0049107.00091329c.5490631 0 .9950893-.44783123.9950893-1.00275046v-5.994422c0-.55646537-.4450595-1.00275046-.9950893-1.00275046h-14.00982141c-.54906309 0-.99508929.44783123-.99508929 1.00275046v5.9971821c0 .66666024.33333333.99999036 1 .99999036l2-.00091329v1l-2 .0009037c-1 0-2-.99999041-2-1.99998077v-5.9971821c0-1.10608322.8926228-2.00274083 1.99508929-2.00274083zm-8.5049107 2.9999711c.27614237 0 .5.22385547.5.5 0 .2761349-.22385763.5-.5.5h-4c-.27614237 0-.5-.2238651-.5-.5 0-.27614453.22385763-.5.5-.5zm3 0c.2761424 0 .5.22385547.5.5 0 .2761349-.2238576.5-.5.5h-1c-.27614237 0-.5-.2238651-.5-.5 0-.27614453.22385763-.5.5-.5zm4 0c.2761424 0 .5.22385547.5.5 0 .2761349-.2238576.5-.5.5h-2c-.2761424 0-.5-.2238651-.5-.5 0-.27614453.2238576-.5.5-.5z" fill-rule="evenodd"/></symbol><symbol id="icon-close" viewBox="0 0 16 16"><path d="m2.29679575 12.2772478c-.39658757.3965876-.39438847 1.0328109-.00062148 1.4265779.39651227.3965123 1.03246768.3934888 1.42657791-.0006214l4.27724782-4.27724787 4.2772478 4.27724787c.3965876.3965875 1.0328109.3943884 1.4265779.0006214.3965123-.3965122.3934888-1.0324677-.0006214-1.4265779l-4.27724787-4.2772478 4.27724787-4.27724782c.3965875-.39658757.3943884-1.03281091.0006214-1.42657791-.3965122-.39651226-1.0324677-.39348875-1.4265779.00062148l-4.2772478 4.27724782-4.27724782-4.27724782c-.39658757-.39658757-1.03281091-.39438847-1.42657791-.00062148-.39651226.39651227-.39348875 1.03246768.00062148 1.42657791l4.27724782 4.27724782z" fill-rule="evenodd"/></symbol><symbol id="icon-collections" viewBox="0 0 18 18"><path d="m15 4c1.1045695 0 2 .8954305 2 2v9c0 1.1045695-.8954305 2-2 2h-8c-1.1045695 0-2-.8954305-2-2h1c0 .5128358.38604019.9355072.88337887.9932723l.11662113.0067277h8c.5128358 0 .9355072-.3860402.9932723-.8833789l.0067277-.1166211v-9c0-.51283584-.3860402-.93550716-.8833789-.99327227l-.1166211-.00672773h-1v-1zm-4-3c1.1045695 0 2 .8954305 2 2v9c0 1.1045695-.8954305 2-2 2h-8c-1.1045695 0-2-.8954305-2-2v-9c0-1.1045695.8954305-2 2-2zm0 1h-8c-.51283584 0-.93550716.38604019-.99327227.88337887l-.00672773.11662113v9c0 .5128358.38604019.9355072.88337887.9932723l.11662113.0067277h8c.5128358 0 .9355072-.3860402.9932723-.8833789l.0067277-.1166211v-9c0-.51283584-.3860402-.93550716-.8833789-.99327227zm-1.5 7c.27614237 0 .5.22385763.5.5s-.22385763.5-.5.5h-5c-.27614237 0-.5-.22385763-.5-.5s.22385763-.5.5-.5zm0-2c.27614237 0 .5.22385763.5.5s-.22385763.5-.5.5h-5c-.27614237 0-.5-.22385763-.5-.5s.22385763-.5.5-.5zm0-2c.27614237 0 .5.22385763.5.5s-.22385763.5-.5.5h-5c-.27614237 0-.5-.22385763-.5-.5s.22385763-.5.5-.5z" fill-rule="evenodd"/></symbol><symbol id="icon-compare" viewBox="0 0 18 18"><path d="m12 3c3.3137085 0 6 2.6862915 6 6s-2.6862915 6-6 6c-1.0928452 0-2.11744941-.2921742-2.99996061-.8026704-.88181407.5102749-1.90678042.8026704-3.00003939.8026704-3.3137085 0-6-2.6862915-6-6s2.6862915-6 6-6c1.09325897 0 2.11822532.29239547 3.00096303.80325037.88158756-.51107621 1.90619177-.80325037 2.99903697-.80325037zm-6 1c-2.76142375 0-5 2.23857625-5 5 0 2.7614237 2.23857625 5 5 5 .74397391 0 1.44999672-.162488 2.08451611-.4539116-1.27652344-1.1000812-2.08451611-2.7287264-2.08451611-4.5460884s.80799267-3.44600721 2.08434391-4.5463015c-.63434719-.29121054-1.34037-.4536985-2.08434391-.4536985zm6 0c-.7439739 0-1.4499967.16248796-2.08451611.45391156 1.27652341 1.10008123 2.08451611 2.72872644 2.08451611 4.54608844s-.8079927 3.4460072-2.08434391 4.5463015c.63434721.2912105 1.34037001.4536985 2.08434391.4536985 2.7614237 0 5-2.2385763 5-5 0-2.76142375-2.2385763-5-5-5zm-1.4162763 7.0005324h-3.16744736c.15614659.3572676.35283837.6927622.58425872 1.0006671h1.99892988c.23142036-.3079049.42811216-.6433995.58425876-1.0006671zm.4162763-2.0005324h-4c0 .34288501.0345146.67770871.10025909 1.0011864h3.79948181c.0657445-.32347769.1002591-.65830139.1002591-1.0011864zm-.4158423-1.99953894h-3.16831543c-.13859957.31730812-.24521946.651783-.31578599.99935097h3.79988742c-.0705665-.34756797-.1771864-.68204285-.315786-.99935097zm-1.58295822-1.999926-.08316107.06199199c-.34550042.27081213-.65446126.58611297-.91825862.93727862h2.00044041c-.28418626-.37830727-.6207872-.71499149-.99902072-.99927061z" fill-rule="evenodd"/></symbol><symbol id="icon-download-file" viewBox="0 0 18 18"><path d="m10.0046024 0c.5497429 0 1.3179837.32258606 1.707238.71184039l4.5763192 4.57631922c.3931386.39313859.7118404 1.16760135.7118404 1.71431368v8.98899651c0 1.1092806-.8945138 2.0085302-1.9940603 2.0085302h-12.01187942c-1.10128908 0-1.99406028-.8926228-1.99406028-1.9950893v-14.00982141c0-1.10185739.88743329-1.99508929 1.99961498-1.99508929zm0 1h-7.00498742c-.55709576 0-.99961498.44271433-.99961498.99508929v14.00982141c0 .5500396.44491393.9950893.99406028.9950893h12.01187942c.5463747 0 .9940603-.4506622.9940603-1.0085302v-8.98899651c0-.28393444-.2150684-.80332809-.4189472-1.0072069l-4.5763192-4.57631922c-.2038461-.20384606-.718603-.41894717-1.0001312-.41894717zm-1.5046024 4c.27614237 0 .5.21637201.5.49209595v6.14827645l1.7462789-1.77990922c.1933927-.1971171.5125222-.19455839.7001689-.0069117.1932998.19329992.1910058.50899492-.0027774.70277812l-2.59089271 2.5908927c-.19483374.1948337-.51177825.1937771-.70556873-.0000133l-2.59099079-2.5909908c-.19484111-.1948411-.19043735-.5151448-.00279066-.70279146.19329987-.19329987.50465175-.19237083.70018565.00692852l1.74638684 1.78001764v-6.14827695c0-.27177709.23193359-.49209595.5-.49209595z" fill-rule="evenodd"/></symbol><symbol id="icon-download" viewBox="0 0 16 16"><path d="m12.9975267 12.999368c.5467123 0 1.0024733.4478567 1.0024733 1.000316 0 .5563109-.4488226 1.000316-1.0024733 1.000316h-9.99505341c-.54671233 0-1.00247329-.4478567-1.00247329-1.000316 0-.5563109.44882258-1.000316 1.00247329-1.000316zm-4.9975267-11.999368c.55228475 0 1 .44497754 1 .99589209v6.80214418l2.4816273-2.48241149c.3928222-.39294628 1.0219732-.4006883 1.4030652-.01947579.3911302.39125371.3914806 1.02525073-.0001404 1.41699553l-4.17620792 4.17752758c-.39120769.3913313-1.02508144.3917306-1.41671995-.0000316l-4.17639421-4.17771394c-.39122513-.39134876-.39767006-1.01940351-.01657797-1.40061601.39113012-.39125372 1.02337105-.3931606 1.41951349.00310701l2.48183446 2.48261871v-6.80214418c0-.55001601.44386482-.99589209 1-.99589209z" fill-rule="evenodd"/></symbol><symbol id="icon-editors" viewBox="0 0 18 18"><path d="m8.72592184 2.54588137c-.48811714-.34391207-1.08343326-.54588137-1.72592184-.54588137-1.65685425 0-3 1.34314575-3 3 0 1.02947485.5215457 1.96853646 1.3698342 2.51900785l.6301658.40892721v1.02400182l-.79002171.32905522c-1.93395773.8055207-3.20997829 2.7024791-3.20997829 4.8180274v.9009805h-1v-.9009805c0-2.5479714 1.54557359-4.79153984 3.82548288-5.7411543-1.09870406-.71297106-1.82548288-1.95054399-1.82548288-3.3578652 0-2.209139 1.790861-4 4-4 1.09079823 0 2.07961816.43662103 2.80122451 1.1446278-.37707584.09278571-.7373238.22835063-1.07530267.40125357zm-2.72592184 14.45411863h-1v-.9009805c0-2.5479714 1.54557359-4.7915398 3.82548288-5.7411543-1.09870406-.71297106-1.82548288-1.95054399-1.82548288-3.3578652 0-2.209139 1.790861-4 4-4s4 1.790861 4 4c0 1.40732121-.7267788 2.64489414-1.8254829 3.3578652 2.2799093.9496145 3.8254829 3.1931829 3.8254829 5.7411543v.9009805h-1v-.9009805c0-2.1155483-1.2760206-4.0125067-3.2099783-4.8180274l-.7900217-.3290552v-1.02400184l.6301658-.40892721c.8482885-.55047139 1.3698342-1.489533 1.3698342-2.51900785 0-1.65685425-1.3431458-3-3-3-1.65685425 0-3 1.34314575-3 3 0 1.02947485.5215457 1.96853646 1.3698342 2.51900785l.6301658.40892721v1.02400184l-.79002171.3290552c-1.93395773.8055207-3.20997829 2.7024791-3.20997829 4.8180274z" fill-rule="evenodd"/></symbol><symbol id="icon-email" viewBox="0 0 18 18"><path d="m16.0049107 2c1.1018574 0 1.9950893.89706013 1.9950893 2.00585866v9.98828264c0 1.1078052-.8926228 2.0058587-1.9950893 2.0058587h-14.00982141c-1.10185739 0-1.99508929-.8970601-1.99508929-2.0058587v-9.98828264c0-1.10780515.8926228-2.00585866 1.99508929-2.00585866zm0 1h-14.00982141c-.54871518 0-.99508929.44887827-.99508929 1.00585866v9.98828264c0 .5572961.44630695 1.0058587.99508929 1.0058587h14.00982141c.5487152 0 .9950893-.4488783.9950893-1.0058587v-9.98828264c0-.55729607-.446307-1.00585866-.9950893-1.00585866zm-.0049107 2.55749512v1.44250488l-7 4-7-4v-1.44250488l7 4z" fill-rule="evenodd"/></symbol><symbol id="icon-error" viewBox="0 0 18 18"><path d="m9 0c4.9705627 0 9 4.02943725 9 9 0 4.9705627-4.0294373 9-9 9-4.97056275 0-9-4.0294373-9-9 0-4.97056275 4.02943725-9 9-9zm2.8630343 4.71100931-2.8630343 2.86303426-2.86303426-2.86303426c-.39658757-.39658757-1.03281091-.39438847-1.4265779-.00062147-.39651227.39651226-.39348876 1.03246767.00062147 1.4265779l2.86303426 2.86303426-2.86303426 2.8630343c-.39658757.3965875-.39438847 1.0328109-.00062147 1.4265779.39651226.3965122 1.03246767.3934887 1.4265779-.0006215l2.86303426-2.8630343 2.8630343 2.8630343c.3965875.3965876 1.0328109.3943885 1.4265779.0006215.3965122-.3965123.3934887-1.0324677-.0006215-1.4265779l-2.8630343-2.8630343 2.8630343-2.86303426c.3965876-.39658757.3943885-1.03281091.0006215-1.4265779-.3965123-.39651227-1.0324677-.39348876-1.4265779.00062147z" fill-rule="evenodd"/></symbol><symbol id="icon-ethics" viewBox="0 0 18 18"><path d="m6.76384967 1.41421356.83301651-.8330165c.77492941-.77492941 2.03133823-.77492941 2.80626762 0l.8330165.8330165c.3750728.37507276.8837806.58578644 1.4142136.58578644h1.3496361c1.1045695 0 2 .8954305 2 2v1.34963611c0 .53043298.2107137 1.03914081.5857864 1.41421356l.8330165.83301651c.7749295.77492941.7749295 2.03133823 0 2.80626762l-.8330165.8330165c-.3750727.3750728-.5857864.8837806-.5857864 1.4142136v1.3496361c0 1.1045695-.8954305 2-2 2h-1.3496361c-.530433 0-1.0391408.2107137-1.4142136.5857864l-.8330165.8330165c-.77492939.7749295-2.03133821.7749295-2.80626762 0l-.83301651-.8330165c-.37507275-.3750727-.88378058-.5857864-1.41421356-.5857864h-1.34963611c-1.1045695 0-2-.8954305-2-2v-1.3496361c0-.530433-.21071368-1.0391408-.58578644-1.4142136l-.8330165-.8330165c-.77492941-.77492939-.77492941-2.03133821 0-2.80626762l.8330165-.83301651c.37507276-.37507275.58578644-.88378058.58578644-1.41421356v-1.34963611c0-1.1045695.8954305-2 2-2h1.34963611c.53043298 0 1.03914081-.21071368 1.41421356-.58578644zm-1.41421356 1.58578644h-1.34963611c-.55228475 0-1 .44771525-1 1v1.34963611c0 .79564947-.31607052 1.55871121-.87867966 2.12132034l-.8330165.83301651c-.38440512.38440512-.38440512 1.00764896 0 1.39205408l.8330165.83301646c.56260914.5626092.87867966 1.3256709.87867966 2.1213204v1.3496361c0 .5522847.44771525 1 1 1h1.34963611c.79564947 0 1.55871121.3160705 2.12132034.8786797l.83301651.8330165c.38440512.3844051 1.00764896.3844051 1.39205408 0l.83301646-.8330165c.5626092-.5626092 1.3256709-.8786797 2.1213204-.8786797h1.3496361c.5522847 0 1-.4477153 1-1v-1.3496361c0-.7956495.3160705-1.5587112.8786797-2.1213204l.8330165-.83301646c.3844051-.38440512.3844051-1.00764896 0-1.39205408l-.8330165-.83301651c-.5626092-.56260913-.8786797-1.32567087-.8786797-2.12132034v-1.34963611c0-.55228475-.4477153-1-1-1h-1.3496361c-.7956495 0-1.5587112-.31607052-2.1213204-.87867966l-.83301646-.8330165c-.38440512-.38440512-1.00764896-.38440512-1.39205408 0l-.83301651.8330165c-.56260913.56260914-1.32567087.87867966-2.12132034.87867966zm3.58698944 11.4960218c-.02081224.002155-.04199226.0030286-.06345763.002542-.98766446-.0223875-1.93408568-.3063547-2.75885125-.8155622-.23496767-.1450683-.30784554-.4531483-.16277726-.688116.14506827-.2349677.45314827-.3078455.68811595-.1627773.67447084.4164161 1.44758575.6483839 2.25617384.6667123.01759529.0003988.03495764.0017019.05204365.0038639.01713363-.0017748.03452416-.0026845.05212715-.0026845 2.4852814 0 4.5-2.0147186 4.5-4.5 0-1.04888973-.3593547-2.04134635-1.0074477-2.83787157-.1742817-.21419731-.1419238-.5291218.0722736-.70340353.2141973-.17428173.5291218-.14192375.7034035.07227357.7919032.97327203 1.2317706 2.18808682 1.2317706 3.46900153 0 3.0375661-2.4624339 5.5-5.5 5.5-.02146768 0-.04261937-.0013529-.06337445-.0039782zm1.57975095-10.78419583c.2654788.07599731.419084.35281842.3430867.61829728-.0759973.26547885-.3528185.419084-.6182973.3430867-.37560116-.10752146-.76586237-.16587951-1.15568824-.17249193-2.5587807-.00064534-4.58547766 2.00216524-4.58547766 4.49928198 0 .62691557.12797645 1.23496.37274865 1.7964426.11035133.2531347-.0053975.5477984-.25853224.6581497-.25313473.1103514-.54779841-.0053975-.65814974-.2585322-.29947131-.6869568-.45606667-1.43097603-.45606667-2.1960601 0-3.05211432 2.47714695-5.50006595 5.59399617-5.49921198.48576182.00815502.96289603.0795037 1.42238033.21103795zm-1.9766658 6.41091303 2.69835-2.94655317c.1788432-.21040373.4943901-.23598862.7047939-.05714545.2104037.17884318.2359886.49439014.0571454.70479387l-3.01637681 3.34277395c-.18039088.1999106-.48669547.2210637-.69285412.0478478l-1.93095347-1.62240047c-.21213845-.17678204-.24080048-.49206439-.06401844-.70420284.17678204-.21213844.49206439-.24080048.70420284-.06401844z" fill-rule="evenodd"/></symbol><symbol id="icon-expand"><path d="M7.498 11.918a.997.997 0 0 0-.003-1.411.995.995 0 0 0-1.412-.003l-4.102 4.102v-3.51A1 1 0 0 0 .98 10.09.992.992 0 0 0 0 11.092V17c0 .554.448 1.002 1.002 1.002h5.907c.554 0 1.002-.45 1.002-1.003 0-.539-.45-.978-1.006-.978h-3.51zm3.005-5.835a.997.997 0 0 0 .003 1.412.995.995 0 0 0 1.411.003l4.103-4.103v3.51a1 1 0 0 0 1.001 1.006A.992.992 0 0 0 18 6.91V1.002A1 1 0 0 0 17 0h-5.907a1.003 1.003 0 0 0-1.002 1.003c0 .539.45.978 1.006.978h3.51z" fill-rule="evenodd"/></symbol><symbol id="icon-explore" viewBox="0 0 18 18"><path d="m9 17c4.418278 0 8-3.581722 8-8s-3.581722-8-8-8-8 3.581722-8 8 3.581722 8 8 8zm0 1c-4.97056275 0-9-4.0294373-9-9 0-4.97056275 4.02943725-9 9-9 4.9705627 0 9 4.02943725 9 9 0 4.9705627-4.0294373 9-9 9zm0-2.5c-.27614237 0-.5-.2238576-.5-.5s.22385763-.5.5-.5c2.969509 0 5.400504-2.3575119 5.497023-5.31714844.0090007-.27599565.2400359-.49243782.5160315-.48343711.2759957.0090007.4924378.2400359.4834371.51603155-.114093 3.4985237-2.9869632 6.284554-6.4964916 6.284554zm-.29090657-12.99359748c.27587424-.01216621.50937715.20161139.52154336.47748563.01216621.27587423-.20161139.50937715-.47748563.52154336-2.93195733.12930094-5.25315116 2.54886451-5.25315116 5.49456849 0 .27614237-.22385763.5-.5.5s-.5-.22385763-.5-.5c0-3.48142406 2.74307146-6.34074398 6.20909343-6.49359748zm1.13784138 8.04763908-1.2004882-1.20048821c-.19526215-.19526215-.19526215-.51184463 0-.70710678s.51184463-.19526215.70710678 0l1.20048821 1.2004882 1.6006509-4.00162734-4.50670359 1.80268144-1.80268144 4.50670359zm4.10281269-6.50378907-2.6692597 6.67314927c-.1016411.2541026-.3029834.4554449-.557086.557086l-6.67314927 2.6692597 2.66925969-6.67314926c.10164107-.25410266.30298336-.45544495.55708602-.55708602z" fill-rule="evenodd"/></symbol><symbol id="icon-filter" viewBox="0 0 16 16"><path d="m14.9738641 0c.5667192 0 1.0261359.4477136 1.0261359 1 0 .24221858-.0902161.47620768-.2538899.65849851l-5.6938314 6.34147206v5.49997973c0 .3147562-.1520673.6111434-.4104543.7999971l-2.05227171 1.4999945c-.45337535.3313696-1.09655869.2418269-1.4365902-.1999993-.13321514-.1730955-.20522717-.3836284-.20522717-.5999978v-6.99997423l-5.69383133-6.34147206c-.3731872-.41563511-.32996891-1.0473954.09653074-1.41107611.18705584-.15950448.42716133-.2474224.67571519-.2474224zm-5.9218641 8.5h-2.105v6.491l.01238459.0070843.02053271.0015705.01955278-.0070558 2.0532976-1.4990996zm-8.02585008-7.5-.01564945.00240169 5.83249953 6.49759831h2.313l5.836-6.499z"/></symbol><symbol id="icon-home" viewBox="0 0 18 18"><path d="m9 5-6 6v5h4v-4h4v4h4v-5zm7 6.5857864v4.4142136c0 .5522847-.4477153 1-1 1h-5v-4h-2v4h-5c-.55228475 0-1-.4477153-1-1v-4.4142136c-.25592232 0-.51184464-.097631-.70710678-.2928932l-.58578644-.5857864c-.39052429-.3905243-.39052429-1.02368929 0-1.41421358l8.29289322-8.29289322 8.2928932 8.29289322c.3905243.39052429.3905243 1.02368928 0 1.41421358l-.5857864.5857864c-.1952622.1952622-.4511845.2928932-.7071068.2928932zm-7-9.17157284-7.58578644 7.58578644.58578644.5857864 7-6.99999996 7 6.99999996.5857864-.5857864z" fill-rule="evenodd"/></symbol><symbol id="icon-image" viewBox="0 0 18 18"><path d="m10.0046024 0c.5497429 0 1.3179837.32258606 1.707238.71184039l4.5763192 4.57631922c.3931386.39313859.7118404 1.16760135.7118404 1.71431368v8.98899651c0 1.1092806-.8945138 2.0085302-1.9940603 2.0085302h-12.01187942c-1.10128908 0-1.99406028-.8926228-1.99406028-1.9950893v-14.00982141c0-1.10185739.88743329-1.99508929 1.99961498-1.99508929zm-3.49645283 10.1752453-3.89407257 6.7495552c.11705545.048464.24538859.0751995.37998328.0751995h10.60290092l-2.4329715-4.2154691-1.57494129 2.7288098zm8.49779013 6.8247547c.5463747 0 .9940603-.4506622.9940603-1.0085302v-8.98899651c0-.28393444-.2150684-.80332809-.4189472-1.0072069l-4.5763192-4.57631922c-.2038461-.20384606-.718603-.41894717-1.0001312-.41894717h-7.00498742c-.55709576 0-.99961498.44271433-.99961498.99508929v13.98991071l4.50814957-7.81026689 3.08089884 5.33809539 1.57494129-2.7288097 3.5875735 6.2159812zm-3.0059397-11c1.1045695 0 2 .8954305 2 2s-.8954305 2-2 2-2-.8954305-2-2 .8954305-2 2-2zm0 1c-.5522847 0-1 .44771525-1 1s.4477153 1 1 1 1-.44771525 1-1-.4477153-1-1-1z" fill-rule="evenodd"/></symbol><symbol id="icon-info" viewBox="0 0 18 18"><path d="m9 0c4.9705627 0 9 4.02943725 9 9 0 4.9705627-4.0294373 9-9 9-4.97056275 0-9-4.0294373-9-9 0-4.97056275 4.02943725-9 9-9zm0 7h-1.5l-.11662113.00672773c-.49733868.05776511-.88337887.48043643-.88337887.99327227 0 .47338693.32893365.86994729.77070917.97358929l.1126697.01968298.11662113.00672773h.5v3h-.5l-.11662113.0067277c-.42082504.0488782-.76196299.3590206-.85696816.7639815l-.01968298.1126697-.00672773.1166211.00672773.1166211c.04887817.4208251.35902055.761963.76398144.8569682l.1126697.019683.11662113.0067277h3l.1166211-.0067277c.4973387-.0577651.8833789-.4804365.8833789-.9932723 0-.4733869-.3289337-.8699473-.7707092-.9735893l-.1126697-.019683-.1166211-.0067277h-.5v-4l-.00672773-.11662113c-.04887817-.42082504-.35902055-.76196299-.76398144-.85696816l-.1126697-.01968298zm0-3.25c-.69035594 0-1.25.55964406-1.25 1.25s.55964406 1.25 1.25 1.25 1.25-.55964406 1.25-1.25-.55964406-1.25-1.25-1.25z" fill-rule="evenodd"/></symbol><symbol id="icon-institution" viewBox="0 0 18 18"><path d="m7 16.9998189v-2.0003623h4v2.0003623h2v-3.0005434h-8v3.0005434zm-3-10.00181122h-1.52632364c-.27614237 0-.5-.22389817-.5-.50009056 0-.13995446.05863589-.27350497.16166338-.36820841l1.23156713-1.13206327h-2.36690687v12.00217346h3v-2.0003623h-3v-1.0001811h3v-1.0001811h1v-4.00072448h-1zm10 0v2.00036224h-1v4.00072448h1v1.0001811h3v1.0001811h-3v2.0003623h3v-12.00217346h-2.3695309l1.2315671 1.13206327c.2033191.186892.2166633.50325042.0298051.70660631-.0946863.10304615-.2282126.16169266-.3681417.16169266zm3-3.00054336c.5522847 0 1 .44779634 1 1.00018112v13.00235456h-18v-13.00235456c0-.55238478.44771525-1.00018112 1-1.00018112h3.45499992l4.20535144-3.86558216c.19129876-.17584288.48537447-.17584288.67667324 0l4.2053514 3.86558216zm-4 3.00054336h-8v1.00018112h8zm-2 6.00108672h1v-4.00072448h-1zm-1 0v-4.00072448h-2v4.00072448zm-3 0v-4.00072448h-1v4.00072448zm8-4.00072448c.5522847 0 1 .44779634 1 1.00018112v2.00036226h-2v-2.00036226c0-.55238478.4477153-1.00018112 1-1.00018112zm-12 0c.55228475 0 1 .44779634 1 1.00018112v2.00036226h-2v-2.00036226c0-.55238478.44771525-1.00018112 1-1.00018112zm5.99868798-7.81907007-5.24205601 4.81852671h10.48411203zm.00131202 3.81834559c-.55228475 0-1-.44779634-1-1.00018112s.44771525-1.00018112 1-1.00018112 1 .44779634 1 1.00018112-.44771525 1.00018112-1 1.00018112zm-1 11.00199236v1.0001811h2v-1.0001811z" fill-rule="evenodd"/></symbol><symbol id="icon-location" viewBox="0 0 18 18"><path d="m9.39521328 16.2688008c.79596342-.7770119 1.59208152-1.6299956 2.33285652-2.5295081 1.4020032-1.7024324 2.4323601-3.3624519 2.9354918-4.871847.2228715-.66861448.3364384-1.29323246.3364384-1.8674457 0-3.3137085-2.6862915-6-6-6-3.36356866 0-6 2.60156856-6 6 0 .57421324.11356691 1.19883122.3364384 1.8674457.50313169 1.5093951 1.53348863 3.1694146 2.93549184 4.871847.74077492.8995125 1.53689309 1.7524962 2.33285648 2.5295081.13694479.1336842.26895677.2602648.39521328.3793207.12625651-.1190559.25826849-.2456365.39521328-.3793207zm-.39521328 1.7311992s-7-6-7-11c0-4 3.13400675-7 7-7 3.8659932 0 7 3.13400675 7 7 0 5-7 11-7 11zm0-8c-1.65685425 0-3-1.34314575-3-3s1.34314575-3 3-3c1.6568542 0 3 1.34314575 3 3s-1.3431458 3-3 3zm0-1c1.1045695 0 2-.8954305 2-2s-.8954305-2-2-2-2 .8954305-2 2 .8954305 2 2 2z" fill-rule="evenodd"/></symbol><symbol id="icon-minus" viewBox="0 0 16 16"><path d="m2.00087166 7h11.99825664c.5527662 0 1.0008717.44386482 1.0008717 1 0 .55228475-.4446309 1-1.0008717 1h-11.99825664c-.55276616 0-1.00087166-.44386482-1.00087166-1 0-.55228475.44463086-1 1.00087166-1z" fill-rule="evenodd"/></symbol><symbol id="icon-newsletter" viewBox="0 0 18 18"><path d="m9 11.8482489 2-1.1428571v-1.7053918h-4v1.7053918zm-3-1.7142857v-2.1339632h6v2.1339632l3-1.71428574v-6.41967746h-12v6.41967746zm10-5.3839632 1.5299989.95624934c.2923814.18273835.4700011.50320827.4700011.8479983v8.44575236c0 1.1045695-.8954305 2-2 2h-14c-1.1045695 0-2-.8954305-2-2v-8.44575236c0-.34479003.1776197-.66525995.47000106-.8479983l1.52999894-.95624934v-2.75c0-.55228475.44771525-1 1-1h12c.5522847 0 1 .44771525 1 1zm0 1.17924764v3.07075236l-7 4-7-4v-3.07075236l-1 .625v8.44575236c0 .5522847.44771525 1 1 1h14c.5522847 0 1-.4477153 1-1v-8.44575236zm-10-1.92924764h6v1h-6zm-1 2h8v1h-8z" fill-rule="evenodd"/></symbol><symbol id="icon-orcid" viewBox="0 0 18 18"><path d="m9 1c4.418278 0 8 3.581722 8 8s-3.581722 8-8 8-8-3.581722-8-8 3.581722-8 8-8zm-2.90107518 5.2732337h-1.41865256v7.1712107h1.41865256zm4.55867178.02508949h-2.99247027v7.14612121h2.91062487c.7673039 0 1.4476365-.1483432 2.0410182-.445034s1.0511995-.7152915 1.3734671-1.2558144c.3222677-.540523.4833991-1.1603247.4833991-1.85942385 0-.68545815-.1602789-1.30270225-.4808414-1.85175082-.3205625-.54904856-.7707074-.97532211-1.3504481-1.27883343-.5797408-.30351132-1.2413173-.45526471-1.9847495-.45526471zm-.1892674 1.07933542c.7877654 0 1.4143875.22336734 1.8798852.67010873.4654977.44674138.698243 1.05546001.698243 1.82617415 0 .74343221-.2310402 1.34447791-.6931277 1.80315511-.4620874.4586773-1.0750688.6880124-1.8389625.6880124h-1.46810075v-4.98745039zm-5.08652545-3.71099194c-.21825533 0-.410525.08444276-.57681478.25333081-.16628977.16888806-.24943341.36245684-.24943341.58071218 0 .22345188.08314364.41961891.24943341.58850696.16628978.16888806.35855945.25333082.57681478.25333082.233845 0 .43390938-.08314364.60019916-.24943342.16628978-.16628977.24943342-.36375592.24943342-.59240436 0-.233845-.08314364-.43131115-.24943342-.59240437s-.36635416-.24163862-.60019916-.24163862z" fill-rule="evenodd"/></symbol><symbol id="icon-plus" viewBox="0 0 16 16"><path d="m2.00087166 7h4.99912834v-4.99912834c0-.55276616.44386482-1.00087166 1-1.00087166.55228475 0 1 .44463086 1 1.00087166v4.99912834h4.9991283c.5527662 0 1.0008717.44386482 1.0008717 1 0 .55228475-.4446309 1-1.0008717 1h-4.9991283v4.9991283c0 .5527662-.44386482 1.0008717-1 1.0008717-.55228475 0-1-.4446309-1-1.0008717v-4.9991283h-4.99912834c-.55276616 0-1.00087166-.44386482-1.00087166-1 0-.55228475.44463086-1 1.00087166-1z" fill-rule="evenodd"/></symbol><symbol id="icon-print" viewBox="0 0 18 18"><path d="m16.0049107 5h-14.00982141c-.54941618 0-.99508929.4467783-.99508929.99961498v6.00077002c0 .5570958.44271433.999615.99508929.999615h1.00491071v-3h12v3h1.0049107c.5494162 0 .9950893-.4467783.9950893-.999615v-6.00077002c0-.55709576-.4427143-.99961498-.9950893-.99961498zm-2.0049107-1v-2.00208688c0-.54777062-.4519464-.99791312-1.0085302-.99791312h-7.9829396c-.55661731 0-1.0085302.44910695-1.0085302.99791312v2.00208688zm1 10v2.0018986c0 1.103521-.9019504 1.9981014-2.0085302 1.9981014h-7.9829396c-1.1092806 0-2.0085302-.8867064-2.0085302-1.9981014v-2.0018986h-1.00491071c-1.10185739 0-1.99508929-.8874333-1.99508929-1.999615v-6.00077002c0-1.10435686.8926228-1.99961498 1.99508929-1.99961498h1.00491071v-2.00208688c0-1.10341695.90195036-1.99791312 2.0085302-1.99791312h7.9829396c1.1092806 0 2.0085302.89826062 2.0085302 1.99791312v2.00208688h1.0049107c1.1018574 0 1.9950893.88743329 1.9950893 1.99961498v6.00077002c0 1.1043569-.8926228 1.999615-1.9950893 1.999615zm-1-3h-10v5.0018986c0 .5546075.44702548.9981014 1.0085302.9981014h7.9829396c.5565964 0 1.0085302-.4491701 1.0085302-.9981014zm-9 1h8v1h-8zm0 2h5v1h-5zm9-5c-.5522847 0-1-.44771525-1-1s.4477153-1 1-1 1 .44771525 1 1-.4477153 1-1 1z" fill-rule="evenodd"/></symbol><symbol id="icon-search" viewBox="0 0 22 22"><path d="M21.697 20.261a1.028 1.028 0 01.01 1.448 1.034 1.034 0 01-1.448-.01l-4.267-4.267A9.812 9.811 0 010 9.812a9.812 9.811 0 1117.43 6.182zM9.812 18.222A8.41 8.41 0 109.81 1.403a8.41 8.41 0 000 16.82z" fill-rule="evenodd"/></symbol><symbol id="icon-social-facebook" viewBox="0 0 24 24"><path d="m6.00368507 20c-1.10660471 0-2.00368507-.8945138-2.00368507-1.9940603v-12.01187942c0-1.10128908.89451376-1.99406028 1.99406028-1.99406028h12.01187942c1.1012891 0 1.9940603.89451376 1.9940603 1.99406028v12.01187942c0 1.1012891-.88679 1.9940603-2.0032184 1.9940603h-2.9570132v-6.1960818h2.0797387l.3114113-2.414723h-2.39115v-1.54164807c0-.69911803.1941355-1.1755439 1.1966615-1.1755439l1.2786739-.00055875v-2.15974763l-.2339477-.02492088c-.3441234-.03134957-.9500153-.07025255-1.6293054-.07025255-1.8435726 0-3.1057323 1.12531866-3.1057323 3.19187953v1.78079225h-2.0850778v2.414723h2.0850778v6.1960818z" fill-rule="evenodd"/></symbol><symbol id="icon-social-twitter" viewBox="0 0 24 24"><path d="m18.8767135 6.87445248c.7638174-.46908424 1.351611-1.21167363 1.6250764-2.09636345-.7135248.43394112-1.50406.74870123-2.3464594.91677702-.6695189-.73342162-1.6297913-1.19486605-2.6922204-1.19486605-2.0399895 0-3.6933555 1.69603749-3.6933555 3.78628909 0 .29642457.0314329.58673729.0942985.8617704-3.06469922-.15890802-5.78835241-1.66547825-7.60988389-3.9574208-.3174714.56076194-.49978171 1.21167363-.49978171 1.90536824 0 1.31404706.65223085 2.47224203 1.64236444 3.15218497-.60350999-.0198635-1.17401554-.1925232-1.67222562-.47366811v.04583885c0 1.83355406 1.27302891 3.36609966 2.96411421 3.71294696-.31118484.0886217-.63651445.1329326-.97441718.1329326-.2357461 0-.47149219-.0229194-.69466516-.0672303.47149219 1.5065703 1.83253297 2.6036468 3.44975116 2.632678-1.2651707 1.0160946-2.85724264 1.6196394-4.5891906 1.6196394-.29861172 0-.59093688-.0152796-.88011875-.0504227 1.63450624 1.0726291 3.57548241 1.6990934 5.66104951 1.6990934 6.79263079 0 10.50641749-5.7711113 10.50641749-10.7751859l-.0094298-.48894775c.7229547-.53478659 1.3516109-1.20250585 1.8419628-1.96190282-.6632323.30100846-1.3751855.50422736-2.1217148.59590507z" fill-rule="evenodd"/></symbol><symbol id="icon-social-youtube" viewBox="0 0 24 24"><path d="m10.1415 14.3973208-.0005625-5.19318431 4.863375 2.60554491zm9.963-7.92753362c-.6845625-.73643756-1.4518125-.73990314-1.803375-.7826454-2.518875-.18714178-6.2971875-.18714178-6.2971875-.18714178-.007875 0-3.7861875 0-6.3050625.18714178-.352125.04274226-1.1188125.04620784-1.8039375.7826454-.5394375.56084773-.7149375 1.8344515-.7149375 1.8344515s-.18 1.49597903-.18 2.99138042v1.4024082c0 1.495979.18 2.9913804.18 2.9913804s.1755 1.2736038.7149375 1.8344515c.685125.7364376 1.5845625.7133337 1.9850625.7901542 1.44.1420891 6.12.1859866 6.12.1859866s3.78225-.005776 6.301125-.1929178c.3515625-.0433198 1.1188125-.0467854 1.803375-.783223.5394375-.5608477.7155-1.8344515.7155-1.8344515s.18-1.4954014.18-2.9913804v-1.4024082c0-1.49540139-.18-2.99138042-.18-2.99138042s-.1760625-1.27360377-.7155-1.8344515z" fill-rule="evenodd"/></symbol><symbol id="icon-subject-medicine" viewBox="0 0 18 18"><path d="m12.5 8h-6.5c-1.65685425 0-3 1.34314575-3 3v1c0 1.6568542 1.34314575 3 3 3h1v-2h-.5c-.82842712 0-1.5-.6715729-1.5-1.5s.67157288-1.5 1.5-1.5h1.5 2 1 2c1.6568542 0 3-1.34314575 3-3v-1c0-1.65685425-1.3431458-3-3-3h-2v2h1.5c.8284271 0 1.5.67157288 1.5 1.5s-.6715729 1.5-1.5 1.5zm-5.5-1v-1h-3.5c-1.38071187 0-2.5-1.11928813-2.5-2.5s1.11928813-2.5 2.5-2.5h1.02786405c.46573528 0 .92507448.10843528 1.34164078.31671843l1.13382424.56691212c.06026365-1.05041141.93116291-1.88363055 1.99667093-1.88363055 1.1045695 0 2 .8954305 2 2h2c2.209139 0 4 1.790861 4 4v1c0 2.209139-1.790861 4-4 4h-2v1h2c1.1045695 0 2 .8954305 2 2s-.8954305 2-2 2h-2c0 1.1045695-.8954305 2-2 2s-2-.8954305-2-2h-1c-2.209139 0-4-1.790861-4-4v-1c0-2.209139 1.790861-4 4-4zm0-2v-2.05652691c-.14564246-.03538148-.28733393-.08714006-.42229124-.15461871l-1.15541752-.57770876c-.27771087-.13885544-.583937-.21114562-.89442719-.21114562h-1.02786405c-.82842712 0-1.5.67157288-1.5 1.5s.67157288 1.5 1.5 1.5zm4 1v1h1.5c.2761424 0 .5-.22385763.5-.5s-.2238576-.5-.5-.5zm-1 1v-5c0-.55228475-.44771525-1-1-1s-1 .44771525-1 1v5zm-2 4v5c0 .5522847.44771525 1 1 1s1-.4477153 1-1v-5zm3 2v2h2c.5522847 0 1-.4477153 1-1s-.4477153-1-1-1zm-4-1v-1h-.5c-.27614237 0-.5.2238576-.5.5s.22385763.5.5.5zm-3.5-9h1c.27614237 0 .5.22385763.5.5s-.22385763.5-.5.5h-1c-.27614237 0-.5-.22385763-.5-.5s.22385763-.5.5-.5z" fill-rule="evenodd"/></symbol><symbol id="icon-success" viewBox="0 0 18 18"><path d="m9 0c4.9705627 0 9 4.02943725 9 9 0 4.9705627-4.0294373 9-9 9-4.97056275 0-9-4.0294373-9-9 0-4.97056275 4.02943725-9 9-9zm3.4860198 4.98163161-4.71802968 5.50657859-2.62834168-2.02300024c-.42862421-.36730544-1.06564993-.30775346-1.42283677.13301307-.35718685.44076653-.29927542 1.0958383.12934879 1.46314377l3.40735508 2.7323063c.42215801.3385221 1.03700951.2798252 1.38749189-.1324571l5.38450527-6.33394549c.3613513-.43716226.3096573-1.09278382-.115462-1.46437175-.4251192-.37158792-1.0626796-.31842941-1.4240309.11873285z" fill-rule="evenodd"/></symbol><symbol id="icon-table" viewBox="0 0 18 18"><path d="m16.0049107 2c1.1018574 0 1.9950893.89706013 1.9950893 2.00585866v9.98828264c0 1.1078052-.8926228 2.0058587-1.9950893 2.0058587l-4.0059107-.001.001.001h-1l-.001-.001h-5l.001.001h-1l-.001-.001-3.00391071.001c-1.10185739 0-1.99508929-.8970601-1.99508929-2.0058587v-9.98828264c0-1.10780515.8926228-2.00585866 1.99508929-2.00585866zm-11.0059107 5h-3.999v6.9941413c0 .5572961.44630695 1.0058587.99508929 1.0058587h3.00391071zm6 0h-5v8h5zm5.0059107-4h-4.0059107v3h5.001v1h-5.001v7.999l4.0059107.001c.5487152 0 .9950893-.4488783.9950893-1.0058587v-9.98828264c0-.55729607-.446307-1.00585866-.9950893-1.00585866zm-12.5049107 9c.27614237 0 .5.2238576.5.5s-.22385763.5-.5.5h-1c-.27614237 0-.5-.2238576-.5-.5s.22385763-.5.5-.5zm12 0c.2761424 0 .5.2238576.5.5s-.2238576.5-.5.5h-2c-.2761424 0-.5-.2238576-.5-.5s.2238576-.5.5-.5zm-6 0c.27614237 0 .5.2238576.5.5s-.22385763.5-.5.5h-2c-.27614237 0-.5-.2238576-.5-.5s.22385763-.5.5-.5zm-6-2c.27614237 0 .5.2238576.5.5s-.22385763.5-.5.5h-1c-.27614237 0-.5-.2238576-.5-.5s.22385763-.5.5-.5zm12 0c.2761424 0 .5.2238576.5.5s-.2238576.5-.5.5h-2c-.2761424 0-.5-.2238576-.5-.5s.2238576-.5.5-.5zm-6 0c.27614237 0 .5.2238576.5.5s-.22385763.5-.5.5h-2c-.27614237 0-.5-.2238576-.5-.5s.22385763-.5.5-.5zm-6-2c.27614237 0 .5.22385763.5.5s-.22385763.5-.5.5h-1c-.27614237 0-.5-.22385763-.5-.5s.22385763-.5.5-.5zm12 0c.2761424 0 .5.22385763.5.5s-.2238576.5-.5.5h-2c-.2761424 0-.5-.22385763-.5-.5s.2238576-.5.5-.5zm-6 0c.27614237 0 .5.22385763.5.5s-.22385763.5-.5.5h-2c-.27614237 0-.5-.22385763-.5-.5s.22385763-.5.5-.5zm1.499-5h-5v3h5zm-6 0h-3.00391071c-.54871518 0-.99508929.44887827-.99508929 1.00585866v1.99414134h3.999z" fill-rule="evenodd"/></symbol><symbol id="icon-tick-circle" viewBox="0 0 24 24"><path d="m12 2c5.5228475 0 10 4.4771525 10 10s-4.4771525 10-10 10-10-4.4771525-10-10 4.4771525-10 10-10zm0 1c-4.97056275 0-9 4.02943725-9 9 0 4.9705627 4.02943725 9 9 9 4.9705627 0 9-4.0294373 9-9 0-4.97056275-4.0294373-9-9-9zm4.2199868 5.36606669c.3613514-.43716226.9989118-.49032077 1.424031-.11873285s.4768133 1.02720949.115462 1.46437175l-6.093335 6.94397871c-.3622945.4128716-.9897871.4562317-1.4054264.0971157l-3.89719065-3.3672071c-.42862421-.3673054-.48653564-1.0223772-.1293488-1.4631437s.99421256-.5003185 1.42283677-.1330131l3.11097438 2.6987741z" fill-rule="evenodd"/></symbol><symbol id="icon-tick" viewBox="0 0 16 16"><path d="m6.76799012 9.21106946-3.1109744-2.58349728c-.42862421-.35161617-1.06564993-.29460792-1.42283677.12733148s-.29927541 1.04903009.1293488 1.40064626l3.91576307 3.23873978c.41034319.3393961 1.01467563.2976897 1.37450571-.0948578l6.10568327-6.660841c.3613513-.41848908.3096572-1.04610608-.115462-1.4018218-.4251192-.35571573-1.0626796-.30482786-1.424031.11366122z" fill-rule="evenodd"/></symbol><symbol id="icon-update" viewBox="0 0 18 18"><path d="m1 13v1c0 .5522847.44771525 1 1 1h14c.5522847 0 1-.4477153 1-1v-1h-1v-10h-14v10zm16-1h1v2c0 1.1045695-.8954305 2-2 2h-14c-1.1045695 0-2-.8954305-2-2v-2h1v-9c0-.55228475.44771525-1 1-1h14c.5522847 0 1 .44771525 1 1zm-1 0v1h-4.5857864l-1 1h-2.82842716l-1-1h-4.58578644v-1h5l1 1h2l1-1zm-13-8h12v7h-12zm1 1v5h10v-5zm1 1h4v1h-4zm0 2h4v1h-4z" fill-rule="evenodd"/></symbol><symbol id="icon-upload" viewBox="0 0 18 18"><path d="m10.0046024 0c.5497429 0 1.3179837.32258606 1.707238.71184039l4.5763192 4.57631922c.3931386.39313859.7118404 1.16760135.7118404 1.71431368v8.98899651c0 1.1092806-.8945138 2.0085302-1.9940603 2.0085302h-12.01187942c-1.10128908 0-1.99406028-.8926228-1.99406028-1.9950893v-14.00982141c0-1.10185739.88743329-1.99508929 1.99961498-1.99508929zm0 1h-7.00498742c-.55709576 0-.99961498.44271433-.99961498.99508929v14.00982141c0 .5500396.44491393.9950893.99406028.9950893h12.01187942c.5463747 0 .9940603-.4506622.9940603-1.0085302v-8.98899651c0-.28393444-.2150684-.80332809-.4189472-1.0072069l-4.5763192-4.57631922c-.2038461-.20384606-.718603-.41894717-1.0001312-.41894717zm-1.85576936 4.14572769c.19483374-.19483375.51177826-.19377714.70556874.00001334l2.59099082 2.59099079c.1948411.19484112.1904373.51514474.0027906.70279143-.1932998.19329987-.5046517.19237083-.7001856-.00692852l-1.74638687-1.7800176v6.14827687c0 .2717771-.23193359.492096-.5.492096-.27614237 0-.5-.216372-.5-.492096v-6.14827641l-1.74627892 1.77990922c-.1933927.1971171-.51252214.19455839-.70016883.0069117-.19329987-.19329988-.19100584-.50899493.00277731-.70277808z" fill-rule="evenodd"/></symbol><symbol id="icon-video" viewBox="0 0 18 18"><path d="m16.0049107 2c1.1018574 0 1.9950893.89706013 1.9950893 2.00585866v9.98828264c0 1.1078052-.8926228 2.0058587-1.9950893 2.0058587h-14.00982141c-1.10185739 0-1.99508929-.8970601-1.99508929-2.0058587v-9.98828264c0-1.10780515.8926228-2.00585866 1.99508929-2.00585866zm0 1h-14.00982141c-.54871518 0-.99508929.44887827-.99508929 1.00585866v9.98828264c0 .5572961.44630695 1.0058587.99508929 1.0058587h14.00982141c.5487152 0 .9950893-.4488783.9950893-1.0058587v-9.98828264c0-.55729607-.446307-1.00585866-.9950893-1.00585866zm-8.30912922 2.24944486 4.60460462 2.73982242c.9365543.55726659.9290753 1.46522435 0 2.01804082l-4.60460462 2.7398224c-.93655425.5572666-1.69578148.1645632-1.69578148-.8937585v-5.71016863c0-1.05087579.76670616-1.446575 1.69578148-.89375851zm-.67492769.96085624v5.5750128c0 .2995102-.10753745.2442517.16578928.0847713l4.58452283-2.67497259c.3050619-.17799716.3051624-.21655446 0-.39461026l-4.58452283-2.67497264c-.26630747-.15538481-.16578928-.20699944-.16578928.08477139z" fill-rule="evenodd"/></symbol><symbol id="icon-warning" viewBox="0 0 18 18"><path d="m9 11.75c.69035594 0 1.25.5596441 1.25 1.25s-.55964406 1.25-1.25 1.25-1.25-.5596441-1.25-1.25.55964406-1.25 1.25-1.25zm.41320045-7.75c.55228475 0 1.00000005.44771525 1.00000005 1l-.0034543.08304548-.3333333 4c-.043191.51829212-.47645714.91695452-.99654578.91695452h-.15973424c-.52008864 0-.95335475-.3986624-.99654576-.91695452l-.33333333-4c-.04586475-.55037702.36312325-1.03372649.91350028-1.07959124l.04148683-.00259031zm-.41320045 14c-4.97056275 0-9-4.0294373-9-9 0-4.97056275 4.02943725-9 9-9 4.9705627 0 9 4.02943725 9 9 0 4.9705627-4.0294373 9-9 9z" fill-rule="evenodd"/></symbol><symbol id="icon-checklist-banner" viewBox="0 0 56.69 56.69"><path style="fill:none" d="M0 0h56.69v56.69H0z"/><clipPath id="b"><use xlink:href="#a" style="overflow:visible"/></clipPath><path d="M21.14 34.46c0-6.77 5.48-12.26 12.24-12.26s12.24 5.49 12.24 12.26-5.48 12.26-12.24 12.26c-6.76-.01-12.24-5.49-12.24-12.26zm19.33 10.66 10.23 9.22s1.21 1.09 2.3-.12l2.09-2.32s1.09-1.21-.12-2.3l-10.23-9.22m-19.29-5.92c0-4.38 3.55-7.94 7.93-7.94s7.93 3.55 7.93 7.94c0 4.38-3.55 7.94-7.93 7.94-4.38-.01-7.93-3.56-7.93-7.94zm17.58 12.99 4.14-4.81" style="clip-path:url(#b);fill:none;stroke:#01324b;stroke-width:2;stroke-linecap:round"/><path d="M8.26 9.75H28.6M8.26 15.98H28.6m-20.34 6.2h12.5m14.42-5.2V4.86s0-2.93-2.93-2.93H4.13s-2.93 0-2.93 2.93v37.57s0 2.93 2.93 2.93h15.01M8.26 9.75H28.6M8.26 15.98H28.6m-20.34 6.2h12.5" style="clip-path:url(#b);fill:none;stroke:#01324b;stroke-width:2;stroke-linecap:round;stroke-linejoin:round"/></symbol><symbol id="icon-chevron-down" viewBox="0 0 16 16"><path d="m5.58578644 3-3.29289322-3.29289322c-.39052429-.39052429-.39052429-1.02368927 0-1.41421356s1.02368927-.39052429 1.41421356 0l4 4c.39052429.39052429.39052429 1.02368927 0 1.41421356l-4 4c-.39052429.39052429-1.02368927.39052429-1.41421356 0s-.39052429-1.02368927 0-1.41421356z" fill-rule="evenodd" transform="matrix(0 1 -1 0 11 1)"/></symbol><symbol id="icon-eds-i-arrow-right-medium" viewBox="0 0 24 24"><path d="m12.728 3.293 7.98 7.99a.996.996 0 0 1 .281.561l.011.157c0 .32-.15.605-.384.788l-7.908 7.918a1 1 0 0 1-1.416-1.414L17.576 13H4a1 1 0 0 1 0-2h13.598l-6.285-6.293a1 1 0 0 1-.082-1.32l.083-.095a1 1 0 0 1 1.414.001Z"/></symbol><symbol id="icon-eds-i-chevron-down-medium" viewBox="0 0 16 16"><path d="m2.00087166 7h4.99912834v-4.99912834c0-.55276616.44386482-1.00087166 1-1.00087166.55228475 0 1 .44463086 1 1.00087166v4.99912834h4.9991283c.5527662 0 1.0008717.44386482 1.0008717 1 0 .55228475-.4446309 1-1.0008717 1h-4.9991283v4.9991283c0 .5527662-.44386482 1.0008717-1 1.0008717-.55228475 0-1-.4446309-1-1.0008717v-4.9991283h-4.99912834c-.55276616 0-1.00087166-.44386482-1.00087166-1 0-.55228475.44463086-1 1.00087166-1z" fill-rule="evenodd"/></symbol><symbol id="icon-eds-i-chevron-down-small" viewBox="0 0 16 16"><path d="M13.692 5.278a1 1 0 0 1 .03 1.414L9.103 11.51a1.491 1.491 0 0 1-2.188.019L2.278 6.692a1 1 0 0 1 1.444-1.384L8 9.771l4.278-4.463a1 1 0 0 1 1.318-.111l.096.081Z"/></symbol><symbol id="icon-eds-i-chevron-right-medium" viewBox="0 0 10 10"><path d="m5.96738168 4.70639573 2.39518594-2.41447274c.37913917-.38219212.98637524-.38972225 1.35419292-.01894278.37750606.38054586.37784436.99719163-.00013556 1.37821513l-4.03074001 4.06319683c-.37758093.38062133-.98937525.38100976-1.367372-.00003075l-4.03091981-4.06337806c-.37759778-.38063832-.38381821-.99150444-.01600053-1.3622839.37750607-.38054587.98772445-.38240057 1.37006824.00302197l2.39538588 2.4146743.96295325.98624457z" fill-rule="evenodd" transform="matrix(0 -1 1 0 0 10)"/></symbol><symbol id="icon-eds-i-chevron-right-small" viewBox="0 0 10 10"><path d="m5.96738168 4.70639573 2.39518594-2.41447274c.37913917-.38219212.98637524-.38972225 1.35419292-.01894278.37750606.38054586.37784436.99719163-.00013556 1.37821513l-4.03074001 4.06319683c-.37758093.38062133-.98937525.38100976-1.367372-.00003075l-4.03091981-4.06337806c-.37759778-.38063832-.38381821-.99150444-.01600053-1.3622839.37750607-.38054587.98772445-.38240057 1.37006824.00302197l2.39538588 2.4146743.96295325.98624457z" fill-rule="evenodd" transform="matrix(0 -1 1 0 0 10)"/></symbol><symbol id="icon-eds-i-chevron-up-medium" viewBox="0 0 16 16"><path d="m2.00087166 7h11.99825664c.5527662 0 1.0008717.44386482 1.0008717 1 0 .55228475-.4446309 1-1.0008717 1h-11.99825664c-.55276616 0-1.00087166-.44386482-1.00087166-1 0-.55228475.44463086-1 1.00087166-1z" fill-rule="evenodd"/></symbol><symbol id="icon-eds-i-close-medium" viewBox="0 0 16 16"><path d="m2.29679575 12.2772478c-.39658757.3965876-.39438847 1.0328109-.00062148 1.4265779.39651227.3965123 1.03246768.3934888 1.42657791-.0006214l4.27724782-4.27724787 4.2772478 4.27724787c.3965876.3965875 1.0328109.3943884 1.4265779.0006214.3965123-.3965122.3934888-1.0324677-.0006214-1.4265779l-4.27724787-4.2772478 4.27724787-4.27724782c.3965875-.39658757.3943884-1.03281091.0006214-1.42657791-.3965122-.39651226-1.0324677-.39348875-1.4265779.00062148l-4.2772478 4.27724782-4.27724782-4.27724782c-.39658757-.39658757-1.03281091-.39438847-1.42657791-.00062148-.39651226.39651227-.39348875 1.03246768.00062148 1.42657791l4.27724782 4.27724782z" fill-rule="evenodd"/></symbol><symbol id="icon-eds-i-download-medium" viewBox="0 0 16 16"><path d="m12.9975267 12.999368c.5467123 0 1.0024733.4478567 1.0024733 1.000316 0 .5563109-.4488226 1.000316-1.0024733 1.000316h-9.99505341c-.54671233 0-1.00247329-.4478567-1.00247329-1.000316 0-.5563109.44882258-1.000316 1.00247329-1.000316zm-4.9975267-11.999368c.55228475 0 1 .44497754 1 .99589209v6.80214418l2.4816273-2.48241149c.3928222-.39294628 1.0219732-.4006883 1.4030652-.01947579.3911302.39125371.3914806 1.02525073-.0001404 1.41699553l-4.17620792 4.17752758c-.39120769.3913313-1.02508144.3917306-1.41671995-.0000316l-4.17639421-4.17771394c-.39122513-.39134876-.39767006-1.01940351-.01657797-1.40061601.39113012-.39125372 1.02337105-.3931606 1.41951349.00310701l2.48183446 2.48261871v-6.80214418c0-.55001601.44386482-.99589209 1-.99589209z" fill-rule="evenodd"/></symbol><symbol id="icon-eds-i-info-filled-medium" viewBox="0 0 18 18"><path d="m9 0c4.9705627 0 9 4.02943725 9 9 0 4.9705627-4.0294373 9-9 9-4.97056275 0-9-4.0294373-9-9 0-4.97056275 4.02943725-9 9-9zm0 7h-1.5l-.11662113.00672773c-.49733868.05776511-.88337887.48043643-.88337887.99327227 0 .47338693.32893365.86994729.77070917.97358929l.1126697.01968298.11662113.00672773h.5v3h-.5l-.11662113.0067277c-.42082504.0488782-.76196299.3590206-.85696816.7639815l-.01968298.1126697-.00672773.1166211.00672773.1166211c.04887817.4208251.35902055.761963.76398144.8569682l.1126697.019683.11662113.0067277h3l.1166211-.0067277c.4973387-.0577651.8833789-.4804365.8833789-.9932723 0-.4733869-.3289337-.8699473-.7707092-.9735893l-.1126697-.019683-.1166211-.0067277h-.5v-4l-.00672773-.11662113c-.04887817-.42082504-.35902055-.76196299-.76398144-.85696816l-.1126697-.01968298zm0-3.25c-.69035594 0-1.25.55964406-1.25 1.25s.55964406 1.25 1.25 1.25 1.25-.55964406 1.25-1.25-.55964406-1.25-1.25-1.25z" fill-rule="evenodd"/></symbol><symbol id="icon-eds-i-mail-medium" viewBox="0 0 24 24"><path d="m19.462 0c1.413 0 2.538 1.184 2.538 2.619v12.762c0 1.435-1.125 2.619-2.538 2.619h-16.924c-1.413 0-2.538-1.184-2.538-2.619v-12.762c0-1.435 1.125-2.619 2.538-2.619zm.538 5.158-7.378 6.258a2.549 2.549 0 0 1 -3.253-.008l-7.369-6.248v10.222c0 .353.253.619.538.619h16.924c.285 0 .538-.266.538-.619zm-.538-3.158h-16.924c-.264 0-.5.228-.534.542l8.65 7.334c.2.165.492.165.684.007l8.656-7.342-.001-.025c-.044-.3-.274-.516-.531-.516z"/></symbol><symbol id="icon-eds-i-menu-medium" viewBox="0 0 24 24"><path d="M21 4a1 1 0 0 1 0 2H3a1 1 0 1 1 0-2h18Zm-4 7a1 1 0 0 1 0 2H3a1 1 0 0 1 0-2h14Zm4 7a1 1 0 0 1 0 2H3a1 1 0 0 1 0-2h18Z"/></symbol><symbol id="icon-eds-i-search-medium" viewBox="0 0 24 24"><path d="M11 1c5.523 0 10 4.477 10 10 0 2.4-.846 4.604-2.256 6.328l3.963 3.965a1 1 0 0 1-1.414 1.414l-3.965-3.963A9.959 9.959 0 0 1 11 21C5.477 21 1 16.523 1 11S5.477 1 11 1Zm0 2a8 8 0 1 0 0 16 8 8 0 0 0 0-16Z"/></symbol><symbol id="icon-eds-i-user-single-medium" viewBox="0 0 24 24"><path d="M12 1a5 5 0 1 1 0 10 5 5 0 0 1 0-10Zm0 2a3 3 0 1 0 0 6 3 3 0 0 0 0-6Zm-.406 9.008a8.965 8.965 0 0 1 6.596 2.494A9.161 9.161 0 0 1 21 21.025V22a1 1 0 0 1-1 1H4a1 1 0 0 1-1-1v-.985c.05-4.825 3.815-8.777 8.594-9.007Zm.39 1.992-.299.006c-3.63.175-6.518 3.127-6.678 6.775L5 21h13.998l-.009-.268a7.157 7.157 0 0 0-1.97-4.573l-.214-.213A6.967 6.967 0 0 0 11.984 14Z"/></symbol><symbol id="icon-eds-i-warning-filled-medium" viewBox="0 0 18 18"><path d="m9 11.75c.69035594 0 1.25.5596441 1.25 1.25s-.55964406 1.25-1.25 1.25-1.25-.5596441-1.25-1.25.55964406-1.25 1.25-1.25zm.41320045-7.75c.55228475 0 1.00000005.44771525 1.00000005 1l-.0034543.08304548-.3333333 4c-.043191.51829212-.47645714.91695452-.99654578.91695452h-.15973424c-.52008864 0-.95335475-.3986624-.99654576-.91695452l-.33333333-4c-.04586475-.55037702.36312325-1.03372649.91350028-1.07959124l.04148683-.00259031zm-.41320045 14c-4.97056275 0-9-4.0294373-9-9 0-4.97056275 4.02943725-9 9-9 4.9705627 0 9 4.02943725 9 9 0 4.9705627-4.0294373 9-9 9z" fill-rule="evenodd"/></symbol><symbol id="icon-expand-image" viewBox="0 0 18 18"><path d="m7.49754099 11.9178212c.38955542-.3895554.38761957-1.0207846-.00290473-1.4113089-.39324695-.3932469-1.02238878-.3918247-1.41130883-.0029047l-4.10273549 4.1027355.00055454-3.5103985c.00008852-.5603185-.44832171-1.006032-1.00155062-1.0059446-.53903074.0000852-.97857527.4487442-.97866268 1.0021075l-.00093318 5.9072465c-.00008751.553948.44841131 1.001882 1.00174994 1.0017946l5.906983-.0009331c.5539233-.0000875 1.00197907-.4486389 1.00206646-1.0018679.00008515-.5390307-.45026621-.9784332-1.00588841-.9783454l-3.51010549.0005545zm3.00571741-5.83449376c-.3895554.38955541-.3876196 1.02078454.0029047 1.41130883.393247.39324696 1.0223888.39182478 1.4113089.00290473l4.1027355-4.10273549-.0005546 3.5103985c-.0000885.56031852.4483217 1.006032 1.0015506 1.00594461.5390308-.00008516.9785753-.44874418.9786627-1.00210749l.0009332-5.9072465c.0000875-.553948-.4484113-1.00188204-1.0017499-1.00179463l-5.906983.00093313c-.5539233.00008751-1.0019791.44863892-1.0020665 1.00186784-.0000852.53903074.4502662.97843325 1.0058884.97834547l3.5101055-.00055449z" fill-rule="evenodd"/></symbol><symbol id="icon-github" viewBox="0 0 100 100"><path fill-rule="evenodd" clip-rule="evenodd" d="M48.854 0C21.839 0 0 22 0 49.217c0 21.756 13.993 40.172 33.405 46.69 2.427.49 3.316-1.059 3.316-2.362 0-1.141-.08-5.052-.08-9.127-13.59 2.934-16.42-5.867-16.42-5.867-2.184-5.704-5.42-7.17-5.42-7.17-4.448-3.015.324-3.015.324-3.015 4.934.326 7.523 5.052 7.523 5.052 4.367 7.496 11.404 5.378 14.235 4.074.404-3.178 1.699-5.378 3.074-6.6-10.839-1.141-22.243-5.378-22.243-24.283 0-5.378 1.94-9.778 5.014-13.2-.485-1.222-2.184-6.275.486-13.038 0 0 4.125-1.304 13.426 5.052a46.97 46.97 0 0 1 12.214-1.63c4.125 0 8.33.571 12.213 1.63 9.302-6.356 13.427-5.052 13.427-5.052 2.67 6.763.97 11.816.485 13.038 3.155 3.422 5.015 7.822 5.015 13.2 0 18.905-11.404 23.06-22.324 24.283 1.78 1.548 3.316 4.481 3.316 9.126 0 6.6-.08 11.897-.08 13.526 0 1.304.89 2.853 3.316 2.364 19.412-6.52 33.405-24.935 33.405-46.691C97.707 22 75.788 0 48.854 0z"/></symbol><symbol id="icon-springer-arrow-left"><path d="M15 7a1 1 0 000-2H3.385l2.482-2.482a.994.994 0 00.02-1.403 1.001 1.001 0 00-1.417 0L.294 5.292a1.001 1.001 0 000 1.416l4.176 4.177a.991.991 0 001.4.016 1 1 0 00-.003-1.42L3.385 7H15z"/></symbol><symbol id="icon-springer-arrow-right"><path d="M1 7a1 1 0 010-2h11.615l-2.482-2.482a.994.994 0 01-.02-1.403 1.001 1.001 0 011.417 0l4.176 4.177a1.001 1.001 0 010 1.416l-4.176 4.177a.991.991 0 01-1.4.016 1 1 0 01.003-1.42L12.615 7H1z"/></symbol><symbol id="icon-submit-open" viewBox="0 0 16 17"><path d="M12 0c1.10457 0 2 .895431 2 2v5c0 .276142-.223858.5-.5.5S13 7.276142 13 7V2c0-.512836-.38604-.935507-.883379-.993272L12 1H6v3c0 1.10457-.89543 2-2 2H1v8c0 .512836.38604.935507.883379.993272L2 15h6.5c.276142 0 .5.223858.5.5s-.223858.5-.5.5H2c-1.104569 0-2-.89543-2-2V5.828427c0-.530433.210714-1.039141.585786-1.414213L4.414214.585786C4.789286.210714 5.297994 0 5.828427 0H12Zm3.41 11.14c.250899.250899.250274.659726 0 .91-.242954.242954-.649606.245216-.9-.01l-1.863671-1.900337.001043 5.869492c0 .356992-.289839.637138-.647372.637138-.347077 0-.647371-.285256-.647371-.637138l-.001043-5.869492L9.5 12.04c-.253166.258042-.649726.260274-.9.01-.242954-.242954-.252269-.657731 0-.91l2.942184-2.951303c.250908-.250909.66127-.252277.91353-.000017L15.41 11.14ZM5 1.413 1.413 5H4c.552285 0 1-.447715 1-1V1.413ZM11 3c.276142 0 .5.223858.5.5s-.223858.5-.5.5H7.5c-.276142 0-.5-.223858-.5-.5s.223858-.5.5-.5H11Zm0 2c.276142 0 .5.223858.5.5s-.223858.5-.5.5H7.5c-.276142 0-.5-.223858-.5-.5s.223858-.5.5-.5H11Z" fill-rule="nonzero"/></symbol></svg> </div> </footer> <div class="c-site-messages message u-hide u-hide-print c-site-messages--nature-briefing c-site-messages--nature-briefing-email-variant c-site-messages--nature-briefing-redesign-2020 sans-serif " data-component-id="nature-briefing-banner" data-component-expirydays="30" data-component-trigger-scroll-percentage="15" data-track="in-view" data-track-action="in-view" data-track-category="nature briefing" data-track-label="Briefing banner visible: Flagship"> <div class="c-site-messages__banner-large"> <div class="c-site-messages__close-container"> <button class="c-site-messages__close" data-track="click" data-track-category="nature briefing" data-track-label="Briefing banner dismiss: Flagship"> <svg width="25px" height="25px" focusable="false" aria-hidden="true" viewBox="0 0 25 25" version="1.1" xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink"> <title>Close banner</title> <defs></defs> <g stroke="none" stroke-width="1" fill="none" fill-rule="evenodd"> <rect opacity="0" x="0" y="0" width="25" height="25"></rect> <path d="M6.29679575,16.2772478 C5.90020818,16.6738354 5.90240728,17.3100587 6.29617427,17.7038257 C6.69268654,18.100338 7.32864195,18.0973145 7.72275218,17.7032043 L12,13.4259564 L16.2772478,17.7032043 C16.6738354,18.0997918 17.3100587,18.0975927 17.7038257,17.7038257 C18.100338,17.3073135 18.0973145,16.671358 17.7032043,16.2772478 L13.4259564,12 L17.7032043,7.72275218 C18.0997918,7.32616461 18.0975927,6.68994127 17.7038257,6.29617427 C17.3073135,5.89966201 16.671358,5.90268552 16.2772478,6.29679575 L12,10.5740436 L7.72275218,6.29679575 C7.32616461,5.90020818 6.68994127,5.90240728 6.29617427,6.29617427 C5.89966201,6.69268654 5.90268552,7.32864195 6.29679575,7.72275218 L10.5740436,12 L6.29679575,16.2772478 Z" fill="#ffffff"></path> </g> </svg> <span class="visually-hidden">Close</span> </button> </div> <div class="c-site-messages__form-container"> <div class="grid grid-12 last"> <div class="grid grid-4"> <img alt="Nature Briefing" src="/static/images/logos/nature-briefing-logo-n150-white-d81c9da3ec.svg" width="250" height="40"> <p class="c-site-messages--nature-briefing__strapline extra-tight-line-height">Sign up for the <em>Nature Briefing</em> newsletter — what matters in science, free to your inbox daily.</p> </div> <div class="grid grid-8 last"> <form action="https://www.nature.com/briefing/briefing" method="post" data-location="banner" data-track="signup_nature_briefing_banner" data-track-action="transmit-form" data-track-category="nature briefing" data-track-label="Briefing banner submit: Flagship"> <input id="briefing-banner-signup-form-input-track-originReferralPoint" type="hidden" name="track_originReferralPoint" value="MainBriefingBanner"> <input id="briefing-banner-signup-form-input-track-formType" type="hidden" name="track_formType" value="DirectEmailBanner"> <input type="hidden" value="false" name="gdpr_tick" id="gdpr_tick_banner"> <input type="hidden" value="false" name="marketing" id="marketing_input_banner"> <input type="hidden" value="false" name="marketing_tick" id="marketing_tick_banner"> <input type="hidden" value="MainBriefingBanner" name="brieferEntryPoint" id="brieferEntryPoint_banner"> <label class="nature-briefing-banner__email-label" for="emailAddress">Email address</label> <div class="nature-briefing-banner__email-wrapper"> <input class="nature-briefing-banner__email-input box-sizing text14" type="email" id="emailAddress" name="emailAddress" value="" placeholder="e.g. jo.smith@university.ac.uk" required data-test-element="briefing-emailbanner-email-input"> <input type="hidden" value="true" name="N:nature_briefing_daily" id="defaultNewsletter_banner"> <button type="submit" class="nature-briefing-banner__submit-button box-sizing text14" data-test-element="briefing-emailbanner-signup-button">Sign up</button> </div> <div class="nature-briefing-banner__checkbox-wrapper grid grid-12 last"> <input class="nature-briefing-banner__checkbox-checkbox" id="gdpr-briefing-banner-checkbox" type="checkbox" name="gdpr" value="true" data-test-element="briefing-emailbanner-gdpr-checkbox" required> <label class="nature-briefing-banner__checkbox-label box-sizing text13 sans-serif block tighten-line-height" for="gdpr-briefing-banner-checkbox">I agree my information will be processed in accordance with the <em>Nature</em> and Springer Nature Limited <a href="https://www.nature.com/info/privacy">Privacy Policy</a>.</label> </div> </form> </div> </div> </div> </div> <div class="c-site-messages__banner-small"> <div class="c-site-messages__close-container"> <button class="c-site-messages__close" data-track="click" data-track-category="nature briefing" data-track-label="Briefing banner dismiss: Flagship"> <svg width="25px" height="25px" focusable="false" aria-hidden="true" viewBox="0 0 25 25" version="1.1" xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink"> <title>Close banner</title> <defs></defs> <g stroke="none" stroke-width="1" fill="none" fill-rule="evenodd"> <rect opacity="0" x="0" y="0" width="25" height="25"></rect> <path d="M6.29679575,16.2772478 C5.90020818,16.6738354 5.90240728,17.3100587 6.29617427,17.7038257 C6.69268654,18.100338 7.32864195,18.0973145 7.72275218,17.7032043 L12,13.4259564 L16.2772478,17.7032043 C16.6738354,18.0997918 17.3100587,18.0975927 17.7038257,17.7038257 C18.100338,17.3073135 18.0973145,16.671358 17.7032043,16.2772478 L13.4259564,12 L17.7032043,7.72275218 C18.0997918,7.32616461 18.0975927,6.68994127 17.7038257,6.29617427 C17.3073135,5.89966201 16.671358,5.90268552 16.2772478,6.29679575 L12,10.5740436 L7.72275218,6.29679575 C7.32616461,5.90020818 6.68994127,5.90240728 6.29617427,6.29617427 C5.89966201,6.69268654 5.90268552,7.32864195 6.29679575,7.72275218 L10.5740436,12 L6.29679575,16.2772478 Z" fill="#ffffff"></path> </g> </svg> <span class="visually-hidden">Close</span> </button> </div> <div class="c-site-messages__content text14"> <span class="c-site-messages--nature-briefing__strapline strong">Get the most important science stories of the day, free in your inbox.</span> <a class="nature-briefing__link text14 sans-serif" data-track="click" data-track-category="nature briefing" data-track-label="Small-screen banner CTA to site" data-test-element="briefing-banner-link" target="_blank" rel="noreferrer noopener" href="https://www.nature.com/briefing/signup/?brieferEntryPoint=MainBriefingBanner">Sign up for Nature Briefing </a> </div> </div> </div> <noscript> <img hidden src="https://verify.nature.com/verify/nature.png" width="0" height="0" style="display: none" alt=""> </noscript> <script src="//content.readcube.com/ping?doi=10.1038/s41467-019-10957-9&format=js&last_modified=2019-07-02" async></script> </body> </html>