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<!doctype html> <html data-n-head-ssr lang="en" data-n-head="%7B%22lang%22:%7B%22ssr%22:%22en%22%7D%7D"> <head > <link data-n-head="ssr" rel="icon" type="image/png" sizes="16x16" href="https://brand.frontiersin.org/m/ed3f9ce840a03d7/favicon_16-tenantFavicon-Frontiers.png"> <link data-n-head="ssr" rel="icon" type="image/png" sizes="32x32" href="https://brand.frontiersin.org/m/ed3f9ce840a03d7/favicon_32-tenantFavicon-Frontiers.png"> <link data-n-head="ssr" rel="apple-touch-icon" type="image/png" sizes="180x180" href="https://brand.frontiersin.org/m/ed3f9ce840a03d7/favicon_180-tenantFavicon-Frontiers.png"> <title>Frontiers | Endophytic Bacteria From the Roots of the Medicinal Plant Alkanna tinctoria Tausch (Boraginaceae): Exploration of Plant Growth Promoting Properties and Potential Role in the Production of Plant Secondary Metabolites</title><meta data-n-head="ssr" charset="utf-8"><meta data-n-head="ssr" name="viewport" content="width=device-width, initial-scale=1"><meta data-n-head="ssr" data-hid="charset" charset="utf-8"><meta data-n-head="ssr" data-hid="mobile-web-app-capable" name="mobile-web-app-capable" content="yes"><meta data-n-head="ssr" data-hid="apple-mobile-web-app-title" name="apple-mobile-web-app-title" content="Frontiers | Articles"><meta data-n-head="ssr" data-hid="theme-color" name="theme-color" content="#0C4DED"><meta data-n-head="ssr" data-hid="description" property="description" name="description" content="Alkannin and shikonin (A/S) are enantiomeric naphthoquinones produced in the roots of certain plants from the Boraginaceae family such as Lithospermum spp. a..."><meta data-n-head="ssr" data-hid="og:title" property="og:title" name="title" content="Frontiers | Endophytic Bacteria From the Roots of the Medicinal Plant Alkanna tinctoria Tausch (Boraginaceae): Exploration of Plant Growth Promoting Properties and Potential Role in the Production of Plant Secondary Metabolites"><meta data-n-head="ssr" data-hid="og:description" property="og:description" name="description" content="Alkannin and shikonin (A/S) are enantiomeric naphthoquinones produced in the roots of certain plants from the Boraginaceae family such as Lithospermum spp. a..."><meta data-n-head="ssr" data-hid="keywords" name="keywords" content="Endophytes,Isolation,Alkanna tinctoria,Alkannin,Shikonin,hairy roots (Min5- Max 8)"><meta data-n-head="ssr" data-hid="og:site_name" property="og:site_name" name="site_name" content="Frontiers"><meta data-n-head="ssr" data-hid="og:image" property="og:image" name="image" content="https://images-provider.frontiersin.org/api/ipx/w=1200&f=png/https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-g001.jpg"><meta data-n-head="ssr" data-hid="og:type" property="og:type" name="type" content="article"><meta data-n-head="ssr" data-hid="og:url" property="og:url" name="url" content="https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2021.633488/full"><meta data-n-head="ssr" data-hid="twitter:card" name="twitter:card" content="summary_large_image"><meta data-n-head="ssr" data-hid="citation_volume" name="citation_volume" content="12"><meta data-n-head="ssr" data-hid="citation_journal_title" name="citation_journal_title" content="Frontiers in Microbiology"><meta data-n-head="ssr" data-hid="citation_publisher" name="citation_publisher" content="Frontiers"><meta data-n-head="ssr" data-hid="citation_journal_abbrev" name="citation_journal_abbrev" content="Front. Microbiol."><meta data-n-head="ssr" data-hid="citation_issn" name="citation_issn" content="1664-302X"><meta data-n-head="ssr" data-hid="citation_doi" name="citation_doi" content="10.3389/fmicb.2021.633488"><meta data-n-head="ssr" data-hid="citation_firstpage" name="citation_firstpage" content="633488"><meta data-n-head="ssr" data-hid="citation_language" name="citation_language" content="English"><meta data-n-head="ssr" data-hid="citation_title" name="citation_title" content="Endophytic Bacteria From the Roots of the Medicinal Plant Alkanna tinctoria Tausch (Boraginaceae): Exploration of Plant Growth Promoting Properties and Potential Role in the Production of Plant Secondary Metabolites"><meta data-n-head="ssr" data-hid="citation_keywords" name="citation_keywords" content="Endophytes; Isolation; Alkanna tinctoria; Alkannin; Shikonin; hairy roots (Min5- Max 8)"><meta data-n-head="ssr" data-hid="citation_abstract" name="citation_abstract" content="<p>Alkannin and shikonin (A/S) are enantiomeric naphthoquinones produced in the roots of certain plants from the Boraginaceae family such as <italic>Lithospermum</italic> spp. and <italic>Alkanna</italic> spp. They possess antimicrobial, anti-tumoral and wound healing properties. The production of secondary metabolites by <italic>Alkanna tinctoria</italic> might be influenced by its endomicrobiome. To study the interaction between this medicinal plant and its bacterial endophytes, we isolated bacteria from the roots of wild growing <italic>Alkanna tinctoria</italic> collected near to Athens and Thessaloniki in Greece. Representative strains selected by MALDI-TOF mass spectrometry were identified by partial 16S rRNA gene sequence analysis. In total, 197 distinct phylotypes of endophytic bacteria were detected. The most abundant genera recovered were <italic>Pseudomonas</italic>, <italic>Xanthomonas</italic>, <italic>Variovorax</italic>, <italic>Bacillus</italic>, <italic>Inquilinus</italic>, <italic>Pantoea</italic>, and <italic>Stenotrophomonas</italic>. Several bacteria were then tested <italic>in vitro</italic> for their plant growth promoting activity and the production of cell-wall degrading enzymes. Strains of <italic>Pseudomonas</italic>, <italic>Pantoea</italic>, <italic>Bacillus</italic> and <italic>Inquilinus</italic> showed positive plant growth properties whereas those of Bacteroidetes and <italic>Rhizobiaceae</italic> showed pectinase and cellulase activity <italic>in vitro</italic>. In addition, bacterial responses to alkannin and shikonin were investigated through resistance assays. Gram negative bacteria were found to be resistant to the antimicrobial properties of A/S, whereas the Gram positives were sensitive. A selection of bacteria was then tested for the ability to induce A/S production in hairy roots culture of <italic>A. tinctoria</italic>. Four strains belonging to <italic>Chitinophaga</italic> sp., <italic>Allorhizobium</italic> sp., <italic>Duganella</italic> sp., and <italic>Micromonospora</italic> sp., resulted in significantly more A/S in the hairy roots than the uninoculated control. As these bacteria can produce cell-wall degrading enzymes, we hypothesize that the A/S induction may be related with the plant-bacteria interaction during colonization.</p>"><meta data-n-head="ssr" data-hid="citation_pdf_url" name="citation_pdf_url" content="https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2021.633488/pdf"><meta data-n-head="ssr" data-hid="citation_online_date" name="citation_online_date" content="2021/01/13"><meta data-n-head="ssr" data-hid="citation_publication_date" name="citation_publication_date" content="2021/02/03"><meta data-n-head="ssr" data-hid="citation_author_0" name="citation_author" content="Rat, Ang茅lique"><meta data-n-head="ssr" data-hid="citation_author_institution_0" name="citation_author_institution" content="Laboratory of Microbiology, Department Biochemistry and Microbiology, Faculty Sciences, Ghent University, Belgium"><meta data-n-head="ssr" data-hid="citation_author_1" name="citation_author" content="Naranjo, Henry D."><meta data-n-head="ssr" data-hid="citation_author_institution_1" name="citation_author_institution" content="Laboratory of Microbiology, Department Biochemistry and Microbiology, Faculty Sciences, Ghent University, Belgium"><meta data-n-head="ssr" data-hid="citation_author_2" name="citation_author" content="Krigas, Nikos"><meta data-n-head="ssr" data-hid="citation_author_institution_2" name="citation_author_institution" content="Laboratory of Conservation and Evaluation of Native and Floricultural Species, Institute of Plant Breeding and Genetic Resources, Hellenic Agricultural Organization Demeter, Greece"><meta data-n-head="ssr" data-hid="citation_author_3" name="citation_author" content="Grigoriadou, Katerina"><meta data-n-head="ssr" data-hid="citation_author_institution_3" name="citation_author_institution" content="Laboratory of Conservation and Evaluation of Native and Floricultural Species, Institute of Plant Breeding and Genetic Resources, Hellenic Agricultural Organization Demeter, Greece"><meta data-n-head="ssr" data-hid="citation_author_4" name="citation_author" content="Maloupa, Eleni"><meta data-n-head="ssr" data-hid="citation_author_institution_4" name="citation_author_institution" content="Laboratory of Conservation and Evaluation of Native and Floricultural Species, Institute of Plant Breeding and Genetic Resources, Hellenic Agricultural Organization Demeter, Greece"><meta data-n-head="ssr" data-hid="citation_author_5" name="citation_author" content="Alonso, Alicia Varela"><meta data-n-head="ssr" data-hid="citation_author_institution_5" name="citation_author_institution" content="Institut f眉r Pflanzenkultur, Germany"><meta data-n-head="ssr" data-hid="citation_author_6" name="citation_author" content="Schneider, Carolin"><meta data-n-head="ssr" data-hid="citation_author_institution_6" name="citation_author_institution" content="Institut f眉r Pflanzenkultur, Germany"><meta data-n-head="ssr" data-hid="citation_author_7" name="citation_author" content="Papageorgiou, Vassilios P."><meta data-n-head="ssr" data-hid="citation_author_institution_7" name="citation_author_institution" content="Organic Chemistry Laboratory, School of Chemical Engineering, Aristotle University of Thessaloniki and Center of Interdisciplinary Research and Innovation of AUTh (CIRI-AUTh), Natural Products Research Centre of Excellence (NatPro-AUTH), Greece"><meta data-n-head="ssr" data-hid="citation_author_8" name="citation_author" content="Assimopoulou, Andreana N."><meta data-n-head="ssr" data-hid="citation_author_institution_8" name="citation_author_institution" content="Organic Chemistry Laboratory, School of Chemical Engineering, Aristotle University of Thessaloniki and Center of Interdisciplinary Research and Innovation of AUTh (CIRI-AUTh), Natural Products Research Centre of Excellence (NatPro-AUTH), Greece"><meta data-n-head="ssr" data-hid="citation_author_9" name="citation_author" content="Tsafantakis, Nikolaos"><meta data-n-head="ssr" data-hid="citation_author_institution_9" name="citation_author_institution" content="Division of Pharmacognosy and Natural Products Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Greece"><meta data-n-head="ssr" data-hid="citation_author_10" name="citation_author" content="Fokialakis, Nikolas"><meta data-n-head="ssr" data-hid="citation_author_institution_10" name="citation_author_institution" content="Division of Pharmacognosy and Natural Products Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Greece"><meta data-n-head="ssr" data-hid="citation_author_11" name="citation_author" content="Willems, Anne"><meta data-n-head="ssr" data-hid="citation_author_institution_11" name="citation_author_institution" content="Laboratory of Microbiology, Department Biochemistry and Microbiology, Faculty Sciences, Ghent University, Belgium"><meta data-n-head="ssr" data-hid="dc.identifier" name="dc.identifier" 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class="Avatar Avatar--size-32"><img src="https://loop.frontiersin.org/images/profile/476457/32" alt="Aleksa Obradovi膰" class="Avatar__img is-inside-mask"></figure> <div class="ArticleDetailsEditors__ediorInfo__info"><div class="ArticleDetailsEditors__ediorInfo__name"> Aleksa Obradovi膰 </div> <div class="ArticleDetailsEditors__ediorInfo__affiliation"> Faculty of Agriculture, University of Belgrade, Serbia </div></div></a></div></div> <div class="ArticleDetailsEditors"><div class="ArticleDetailsEditors__editors"><div class="ArticleDetailsEditors__title">Reviewed by</div> <a href="https://loop.frontiersin.org/people/360397/overview" data-event="editorInfo-a-carolinaChiellini" class="ArticleDetailsEditors__ediorInfo"><figure class="Avatar Avatar--size-32"><img src="https://loop.frontiersin.org/images/profile/360397/32" alt="Carolina Chiellini" class="Avatar__img is-inside-mask"></figure> <div class="ArticleDetailsEditors__ediorInfo__info"><div class="ArticleDetailsEditors__ediorInfo__name"> Carolina Chiellini </div> <div class="ArticleDetailsEditors__ediorInfo__affiliation"> Pisa Research Area, National Research Council (CNR), Italy </div></div></a><a href="https://loop.frontiersin.org/people/549870/overview" data-event="editorInfo-a-debdulalBanerjee" class="ArticleDetailsEditors__ediorInfo"><figure class="Avatar Avatar--size-32"><img src="https://loop.frontiersin.org/images/profile/549870/32" alt="Debdulal Banerjee" class="Avatar__img is-inside-mask"></figure> <div class="ArticleDetailsEditors__ediorInfo__info"><div class="ArticleDetailsEditors__ediorInfo__name"> Debdulal Banerjee </div> <div class="ArticleDetailsEditors__ediorInfo__affiliation"> Vidyasagar University, India </div></div></a></div></div> <div class="ArticleDetailsGlossary ArticleDetailsGlossary--open"><button class="ArticleDetailsGlossary__header"><div class="ArticleDetailsGlossary__header__title">Table of contents</div> <div 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class="ArticleLayoutHeader__info"><h2 class="ArticleLayoutHeader__info__title">ORIGINAL RESEARCH article</h2> <div class="ArticleLayoutHeader__info__journalDate"><span>Front. Microbiol.</span><span>, 03 February 2021</span></div> <div class="ArticleLayoutHeader__info__journalDate"> Sec. Microbe and Virus Interactions with Plants </div> <div class="ArticleLayoutHeader__info__doiVolume"><span> Volume 12 - 2021 | </span> <a href="https://doi.org/10.3389/fmicb.2021.633488" class="ArticleLayoutHeader__info__doi"> https://doi.org/10.3389/fmicb.2021.633488 </a></div> </div>  </div> <div class="ArticleDetails__main__content"><div class="ArticleDetails__main__content__main ArticleDetails__main__content__main--fullArticle"><div class="JournalAbstract"><div class="JournalAbstract__titleWrapper"><h1>Endophytic Bacteria From the Roots of the Medicinal Plant <i>Alkanna tinctoria</i> Tausch (<i>Boraginaceae</i>): Exploration of Plant Growth Promoting Properties and Potential Role in the Production of Plant Secondary Metabolites</h1> </div> </div> <div class="JournalFullText"><div class="JournalAbstract"> <a id="h1" name="h1"></a> <div class="authors"><span class="author-wrapper"> <a href="https://loop.frontiersin.org/people/1152558" class="user-id-1152558"><img class="pr5" src="https://loop.frontiersin.org/images/profile/1152558/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="\r\nAnglique Rat*">Angélique Rat</a><sup>1*</sup></span><span class="author-wrapper"><a href="https://loop.frontiersin.org/people/1153085" class="user-id-1153085"><img class="pr5" src="https://loop.frontiersin.org/images/profile/1153085/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="Henry D. Naranjo">Henry D. Naranjo</a><sup>1</sup></span><span class="author-wrapper"><a href="https://loop.frontiersin.org/people/389080" class="user-id-389080"><img class="pr5" src="https://loop.frontiersin.org/images/profile/389080/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="Nikos Krigas">Nikos Krigas</a><sup>2</sup></span><span class="author-wrapper"><img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="Katerina Grigoriadou" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">Katerina Grigoriadou<sup>2</sup></span><span class="author-wrapper"><a href="https://loop.frontiersin.org/people/1178870" class="user-id-1178870"><img class="pr5" src="https://loop.frontiersin.org/images/profile/1178870/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="Eleni Maloupa">Eleni Maloupa</a><sup>2</sup></span><span class="author-wrapper"><a href="https://loop.frontiersin.org/people/1205578" class="user-id-1205578"><img class="pr5" src="https://loop.frontiersin.org/images/profile/1205578/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="Alicia Varela Alonso">Alicia Varela Alonso</a><sup>3</sup></span><span class="author-wrapper"><a href="https://loop.frontiersin.org/people/76144" class="user-id-76144"><img class="pr5" src="https://loop.frontiersin.org/images/profile/76144/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="Carolin Schneider">Carolin Schneider</a><sup>3</sup></span><span class="author-wrapper"><img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="Vassilios P. Papageorgiou" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">Vassilios P. Papageorgiou<sup>4</sup></span><span class="author-wrapper"><a href="https://loop.frontiersin.org/people/1178735" class="user-id-1178735"><img class="pr5" src="https://loop.frontiersin.org/images/profile/1178735/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="Andreana N. Assimopoulou">Andreana N. Assimopoulou</a><sup>4</sup></span><span class="author-wrapper"><img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="Nikolaos Tsafantakis" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">Nikolaos Tsafantakis<sup>5</sup></span><span class="author-wrapper"><a href="https://loop.frontiersin.org/people/132946" class="user-id-132946"><img class="pr5" src="https://loop.frontiersin.org/images/profile/132946/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="Nikolas Fokialakis">Nikolas Fokialakis</a><sup>5</sup></span><span class="author-wrapper"><a href="https://loop.frontiersin.org/people/282149" class="user-id-282149"><img class="pr5" src="https://loop.frontiersin.org/images/profile/282149/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="Anne Willems">Anne Willems</a><sup>1</sup></span></div> <ul class="notes"> <li><span><sup>1</sup></span>Laboratory of Microbiology, Department Biochemistry and Microbiology, Faculty Sciences, Ghent University, Ghent, Belgium</li> <li><span><sup>2</sup></span>Laboratory of Conservation and Evaluation of Native and Floricultural Species, Institute of Plant Breeding and Genetic Resources, Hellenic Agricultural Organization Demeter, Thessaloniki, Greece</li> <li><span><sup>3</sup></span>Institut für Pflanzenkultur, Schnega, Germany</li> <li><span><sup>4</sup></span>Organic Chemistry Laboratory, School of Chemical Engineering, Aristotle University of Thessaloniki and Center of Interdisciplinary Research and Innovation of AUTh (CIRI-AUTh), Natural Products Research Centre of Excellence (NatPro-AUTH), Thessaloniki, Greece</li> <li><span><sup>5</sup></span>Division of Pharmacognosy and Natural Products Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece</li> </ul> <p class="mb0">Alkannin and shikonin (A/S) are enantiomeric naphthoquinones produced in the roots of certain plants from the Boraginaceae family such as <i>Lithospermum</i> spp. and <i>Alkanna</i> spp. They possess antimicrobial, anti-tumoral and wound healing properties. The production of secondary metabolites by <i>Alkanna tinctoria</i> might be influenced by its endomicrobiome. To study the interaction between this medicinal plant and its bacterial endophytes, we isolated bacteria from the roots of wild growing <i>Alkanna tinctoria</i> collected near to Athens and Thessaloniki in Greece. Representative strains selected by MALDI-TOF mass spectrometry were identified by partial 16S rRNA gene sequence analysis. In total, 197 distinct phylotypes of endophytic bacteria were detected. The most abundant genera recovered were <i>Pseudomonas</i>, <i>Xanthomonas</i>, <i>Variovorax</i>, <i>Bacillus</i>, <i>Inquilinus</i>, <i>Pantoea</i>, and <i>Stenotrophomonas</i>. Several bacteria were then tested <i>in vitro</i> for their plant growth promoting activity and the production of cell-wall degrading enzymes. Strains of <i>Pseudomonas</i>, <i>Pantoea</i>, <i>Bacillus</i> and <i>Inquilinus</i> showed positive plant growth properties whereas those of Bacteroidetes and <i>Rhizobiaceae</i> showed pectinase and cellulase activity <i>in vitro</i>. In addition, bacterial responses to alkannin and shikonin were investigated through resistance assays. Gram negative bacteria were found to be resistant to the antimicrobial properties of A/S, whereas the Gram positives were sensitive. A selection of bacteria was then tested for the ability to induce A/S production in hairy roots culture of <i>A. tinctoria</i>. Four strains belonging to <i>Chitinophaga</i> sp., <i>Allorhizobium</i> sp., <i>Duganella</i> sp., and <i>Micromonospora</i> sp., resulted in significantly more A/S in the hairy roots than the uninoculated control. As these bacteria can produce cell-wall degrading enzymes, we hypothesize that the A/S induction may be related with the plant-bacteria interaction during colonization.</p> <div class="clear"></div> </div> <div class="JournalFullText"> <a id="h2" name="h2"></a><h2>Introduction</h2> <p class="mb15">Plants communicate and interact with a wide variety of microorganisms. They release water-soluble sugars, organic acids, ionic compounds, phenolics, hormones, and other metabolites into the rhizosphere, thus providing nutrients to microorganisms. Due to the richness of nutrients in this soil region, compared to bulk soil, the rhizosphere is enriched with microorganisms, leading to increased microbial interactions (<a href="#B71">Sasse et al., 2018</a>; <a href="#B87">Yu and Hochholdinger, 2018</a>). Rhizospheric microorganisms influence plant growth through soil nutrient recycling and nutrient uptake. For example, bacteria such as <i>Acidobacterium</i> sp., <i>Pedobacter</i> sp., <i>Muciliginibacter</i> sp., and <i>Cellulomona</i>s sp. play an important role in the recycling of plant polysaccharides such as cellulose, pectin and lignin (<a href="#B46">López-Mondéjar et al., 2016</a>; <a href="#B66">Poulsen et al., 2016</a>; <a href="#B13">Belova et al., 2018</a>). Several bacteria including those from the genera <i>Pseudomonas</i>, <i>Pantoea</i>, and <i>Bacillus</i> have the ability to solubilize and therefore make accessible insoluble phosphate to plants (<a href="#B26">Ghyselinck et al., 2013</a>). Similarly, rhizobia can provide plants with combined nitrogen via biological nitrogen fixation (<a href="#B48">Mabrouk et al., 2018</a>). Soil microorganisms can also influence plant growth through the secretion of growth hormones such as indole acetic acid (IAA) or ethylene. Indeed, several studies have shown that plant inoculation with IAA-producing bacteria promote plant growth significantly (<a href="#B62">Patten and Glick, 2002</a>; <a href="#B52">Mohite, 2013</a>; <a href="#B18">Chandra et al., 2018</a>). Furthermore, rhizospheric bacteria can play a role in plant defense and metabolite production (<a href="#B40">Lambers et al., 2009</a>; <a href="#B14">Berendsen et al., 2012</a>; <a href="#B31">Huang et al., 2019</a>). They can first compete with pathogens for nutrients and space in the rhizosphere. For instance, siderophore-producing bacteria can contend with soil pathogens for iron uptake and consequently prevent the root colonization by these microorganisms. As iron is essential for the growth of many organisms and is involved in biofilm formation that is needed for successful root colonization, its uptake by beneficial bacteria can prevent pathogen infections (<a href="#B67">Ramey et al., 2004</a>; <a href="#B2">Ahmed and Holmström, 2014</a>). Microorganisms can also produce secondary metabolites with antimicrobial properties. For example, <i>Burkholderia</i> sp. showed antimicrobial activities against the plant pathogens <i>Phytophthora capsici</i>, <i>Fusarium oxysporum</i>, and <i>Rhizoctonia solani</i> through the production of pyrrolnitrin (<a href="#B33">Jung et al., 2018</a>). In addition, some microbes can induce plant defenses. <a href="#B7">Asghari et al. (2020)</a> demonstrated that <i>Pseudomonas</i> sp. Sn48 and <i>Pantoea</i> sp. Sa14 induce plant production of phytoalexins and polyamines resulting in a reduction of the <i>Agrobacterium tumefaciens</i> gall.</p> <p class="mb15">Among the microorganisms interacting with plants, endophytes are defined as those that colonize the internal tissues of plants during the entire or part of their host’s lifecycle without causing external damage (<a href="#B69">Ryan et al., 2008</a>; <a href="#B4">Anjum and Chandra, 2015</a>; <a href="#B58">Orlikowska et al., 2017</a>). Like rhizospheric microorganisms, they can promote plant growth and influence plant metabolites. In the case of medicinal plants, endophytes contribute to or are responsible for their host’s pharmaceutical properties (e.g., antioxidant and/or antimicrobial properties; <a href="#B36">Köberl et al., 2013</a>; <a href="#B16">Brader et al., 2014</a>; <a href="#B49">Maggini et al., 2017</a>). The inoculation of <i>Bacillus subtilis</i> BERA 71 to chickpea increased the plant biomass and reduced the levels of reactive oxygen species and lipid peroxidation under salinity stress. This effect was associated with an enhancement of the activities of enzymatic and non-enzymatic antioxidants (<a href="#B1">Abd_Allah et al., 2017</a>). Endophytes can also influence the antimicrobial activity as well as the production of secondary metabolites in medicinal plants. <a href="#B59">Pandey et al. (2018)</a> showed that endophytic fungi increase the biomass of <i>Withania somnifera</i>, resulting in a higher total plant withanolide content. Moreover, the inoculation of endophytic bacteria stimulated the withanolide biosynthesis pathway by upregulating the expression of key genes within this pathway such as <i>HMGR</i>, <i>DXS</i>, and <i>DXR</i> (<a href="#B59">Pandey et al., 2018</a>). Endophytes of medicinal plants also produce a wide range of bioactive secondary metabolites such as alkaloids, isoprenoids, flavonoids and indoles (<a href="#B77">Tan and Zou, 2001</a>; <a href="#B11">Barman and Bhattacharjee, 2020</a>; <a href="#B53">Monnanda et al., 2020</a>).</p> <p class="mb15">Studies on endophytes are indeed invaluable to the promotion of medicinal plants’ therapeutic properties. <i>Alkanna tinctoria</i> (family <i>Boraginaceae</i>) is a medicinal plant native to countries of the Mediterranean region (<a href="#B76">Strid, 2016</a>). The plant produces quinones and phenolic compounds and has antioxidant activities. Moreover, compared to other <i>Alkanna</i> species, <i>A. tinctoria</i> produces high amounts of alkannin/shikonin (A/S) and their derivatives. These secondary metabolites are enantiomeric naphthoquinones produced by root tissues. They are sequestered to form granules in the phospholipid layer and are accumulated in the apoplastic spaces. Thus, they can be found in the cork layer of mature roots and their accumulation leads to a red or purple coloration of the root (<a href="#B17">Brigham et al., 1999</a>; <a href="#B75">Singh et al., 2010</a>; <a href="#B79">Tatsumi et al., 2016</a>). The A/S derivatives are strongly involved in the antimicrobial activity of the plant and form a chemical barrier against soil-borne microorganisms. They are also known for wound healing, anticancer and anti-inflammatory properties (<a href="#B61">Papageorgiou et al., 1999</a>, <a href="#B60">2008</a>) and they comprise the active pharmaceutical ingredients of strong wound healing medicines approved by the National Organization for Medicines in Greece. Because of these interesting traits, <i>A. tinctoria</i> was chosen for the production of A/S for medical applications (<a href="#B60">Papageorgiou et al., 2008</a>; <a href="#B73">Sengul et al., 2009</a>; <a href="#B82">Tung et al., 2013</a>).</p> <p class="mb0">Despite the medicinal importance of wild-growing <i>A. tinctoria</i> and the potential bioactive properties of its associated bacteria, no studies have been performed so far on its endophytic bacteria and their possible interactions with the plant. The aims of this work were therefore (i) to explore the diversity of endophytic bacteria associated with <i>A. tinctoria</i>, (ii) to screen the isolates for a number of plant-growth promotion properties and for the production of cell-wall degrading enzymes (iii) to evaluate the effect of the A/S produced by the plant on the associated bacteria, and (iv) to test their effect on plant A/S production in a bioassay.</p> <a id="h3" name="h3"></a><h2>Materials and Methods</h2> <h3 class="pt0">Isolation of Root Endophytic Bacteria From Wild-Growing <i>Alkanna tinctoria</i> Plants</h3> <p class="mb15">Three botanical expeditions to collect wild-growing <i>Alkanna tinctoria</i> were undertaken. The first one was conducted in December 2017, in Northern Greece (Seich Sou area close to the Theater of the Earth, Thessaloniki, Greece), using a special collection permit obtained by the Institute of Plant Breeding and Genetic Resources, Hellenic Agricultural Organization Demeter (IPBGR, HAO Demeter) which is issued annually by the Greek Ministry of Environment and Energy. Samples from this expedition were used to optimize the isolation conditions. The wild plants collected were taxonomically identified and they were given the International Plant Exchange Network (IPEN) accession number GR-1-BBGK-18,6081 for their long-term <i>ex situ</i> conservation (including also asexual and <i>in vitro</i> propagation trials) at the premises of IPBGR, HAO Demeter. Two further collections were made in April and May of 2018 in Southern Greece (at the University of Athens, Campus of Zografou, Athens) and Northern Greece (Seich Sou area, Thessaloniki), respectively.</p> <p class="mb15">After each expedition, a bacterial isolation campaign was conducted. Three plants from each of the collections were chosen to explore the diversity of culturable bacterial endophytes. The roots were first cleaned with tap water to remove soil particles. Subsequently, they were immersed in a solution of 70% ethanol for 5 min. After rinsing with sterile water, the root was further sterilized with a solution of 1.4% of NaOCl for 20 min. The root was rinsed again and immersed in 2% Na<sub>2</sub>S<sub>2</sub>O<sub>3</sub> for 10 min to neutralize the effect of bleach. A last rinse with sterile water was performed before testing the efficiency of the sterilization process in order to exclude non-endophytes. To do so, the external surface of the root was imprinted onto a sterile plate containing 869 agar medium (<a href="#B83">Weyens et al., 2012</a>; <a href="#B22">Eevers et al., 2015</a>) before incubation at 28°C. Only roots without microbial growth on the imprints were used for the isolation of endophytic bacteria. The root material was crushed in 10 mL of sterile phosphate buffer saline (PBS) and a 10-fold dilution series was prepared. The dilutions 10<sup>–2</sup>–10<sup>–7</sup> were then plated in triplicate.</p> <p class="mb0">To determine the isolation conditions (medium, incubation time and temperature) that would yield the widest bacterial diversity, during the first isolation campaign a wide selection of media were compared. Nine culture media supplemented with 50 mg/L cycloheximide were tested, including the commonly used media R2A (Difco), 1/10 TSA (Oxoid), and ISP2 (Oxoid), as well as 1/10 869 medium (<a href="#B22">Eevers et al., 2015</a>) which is routinely used for the isolation of endophytes. In addition, 1/10 869 medium supplemented with either an infusion of dried <i>Symphytum officinale</i> (family <i>Boraginaceae</i>) roots or with allantoin was tested. To prepare the former medium supplement, dried <i>S. officinale</i> roots (Bioshop, Gent, Belgium) were infused in boiled water for 10 min (28 g/L). The infusion was then filtered and used to resuspend the dry ingredients of medium 1/10 869. Allantoin was added to medium 1/10 869 at four concentrations (0.32, 1.6, 9, 32 mM). Allantoin is a secondary metabolite found in the root of several members of the <i>Boraginaceae</i> family (<a href="#B22">Eevers et al., 2015</a>; <a href="#B20">Dresler et al., 2017</a>). In this first isolation campaign, plates were incubated at 28°C for 4 days after which all distinct colony types were picked for purification. Plates of the highest dilutions were incubated for an additional 10 days at 20°C to isolate slow growers.</p> <h3>Identification of the Isolates</h3> <p class="mb15">Dereplication and identification of the isolates obtained in the different conditions were performed using MALDI-TOF MS and 16S rRNA gene sequencing. To conduct the MALDI-TOF MS, pure 2nd generation cultures were grown. The proteins were then extracted, spotted in duplicate onto MALDI-TOF target plates and overlaid with matrix solution (10 mg/mL α-cyano-4-hydroxycinnamic acid in acetonitrile-water-trifluoroacetic acid) as previously described (<a href="#B21">Dumolin et al., 2019</a>). The protein profiles were read with the Bruker Microflex<sup>TM</sup> LT/SH system. The programs SPeDE (<a href="#B21">Dumolin et al., 2019</a>) and BioNumerics (Applied Mats) were used to cluster the protein profiles. In SPeDe, each unique spectrum is assigned as a reference and clusters of all similar spectra are generated (<a href="#B21">Dumolin et al., 2019</a>). Thus, strains from which the spectra clustered together were considered as highly similar and only the reference strains were selected for rRNA 16S gene sequencing (<a href="#B32">Jain et al., 2018</a>).</p> <p class="mb0">Genomic DNA was extracted by alkaline lysis according to the method of <a href="#B56">Niemann et al. (1997)</a>. Amplification of the 16S rRNA gene was performed using primers pA (3′-AGAGTTTGATCCTGGCTCAG-5′, forward) and pH (5′-AAGGAGGTGATCCAGCCGCA-3′, reverse). The PCR products were sequenced by Eurofins Genomics, Mix2seq service, with the BKL1 primer (5′-GTATTACCGCGGCTGCTGGCA-3′, reverse) and the sequences obtained were identified with EzTaxon database (<a href="#B86">Yoon et al., 2017</a>). We considered two sequences as belonging to the same species when they were at least 98.7% identical and as belonging to the same genus when they were at least 94.8% identical (<a href="#B54">Moreira and López-García, 2014</a>; <a href="#B84">Yarza et al., 2014</a>).</p> <h3>Plant Growth-Promoting Activity of Endophytic Bacteria</h3> <p class="mb0">To test bacteria <i>in vitro</i> for their plant growth promoting activity, four parameters were evaluated: phosphate solubilization, siderophore production, ACC deaminase activity, and indole acetic acid production.</p> <h4>Phosphate Solubilization</h4> <p class="mb0">NBRIP medium (2.5 g/L Ca<sub>3</sub>(PO<sub>4</sub>); 5 g/L MgCl<sub>2</sub>,6H<sub>2</sub>O; 0.25 g/L MgSO<sub>4</sub>,7H<sub>2</sub>O; 0.2 g/L KCl, 0.1 g/L (NH<sub>4</sub>)<sub>2</sub>SO<sub>4</sub>, and 15 g/L agar) with 10 g/L glucose was used for this test (<a href="#B55">Nautiyal, 1999</a>). The pH of the medium was adjusted to 7 before autoclaving and small Petri dishes were used (diameter 5.5 cm). Dense bacterial suspensions (OD 0.5–0.6) were made in 1 mL of PBS. Then, 10 μL of each suspension was spotted in the middle of each plate. The test was performed in triplicate. The diameter of clear halos around the bacterial growth was measured after 2, 4, 7, and 10 days of incubation at 28°C. The strain R-42086 (<i>Pseudomonas</i> sp.) was used as a positive control (<a href="#B26">Ghyselinck et al., 2013</a>).</p> <h4>Siderophore Production</h4> <p class="mb0">To test the production of siderophores, the CAS (chrome azurol S) blue medium was prepared according to <a href="#B47">Louden et al. (2011)</a>. Small Petri dishes were used (diameter 5.5 cm). Dense bacterial suspensions (OD 0.5–0.6) were made in 1 mL of sterile PBS. Then, 10 μL of each suspension was spotted in the middle of each plate. The test was performed in triplicate. The halo diameter was observed and measured after 2, 4, 7, and 10 days of incubation at 28°C. The strain R-42086 (<i>Pseudomonas</i> sp.) was used as a positive control (<a href="#B26">Ghyselinck et al., 2013</a>).</p> <h4>1-Aminocyclopropane-1-Carboxylate (ACC) Deaminase Activity</h4> <p class="mb0">DFS medium was prepared for the ACC deaminase test following the protocol from <a href="#B63">Penrose and Glick (2003)</a>. The glucose and the citric acid were filter sterilized and added to the autoclaved medium. To conduct the experiment, the bacteria were first grown in DFS medium + 2 g (NH<sub>4</sub>)<sub>2</sub>SO<sub>4</sub> for 72 h at 28°C, 100 rpm. Then, in a 96-well plate, for each strain 15 μL of the liquid culture was added in 135 μL of DFS medium + 3 mM ACC. Each strain was tested in triplicate. The DFS medium without any nitrogen source was used as control. As blanks, the outermost wells of the plate were filled with the culture medium free of bacteria. After 48 h at 28°C, the OD was read at 590 nm. Then, 50 μL of the culture was re-transferred to fresh DFS + 0.3 M ACC. This procedure was repeated twice to exhaust any residual stock of nitrogen. The strain R-42058 <i>(Pseudomonas</i> sp.) was used as a positive control and the ACC deaminase activity was evaluated by comparison with the blank (<a href="#B26">Ghyselinck et al., 2013</a>).</p> <h4>IAA Production</h4> <p class="mb15">Yeast malt extract medium (YM, peptone 5 g/L, yeast extract 3 g/L, malt extract 3 g/L, pH 6.2) was used to test for the production of indole acetic acid (IAA) in liquid culture (<a href="#B5">Apine and Jadhav, 2011</a>; <a href="#B52">Mohite, 2013</a>). Bacteria were grown in R2B medium (Difco) for 72 h at 28°C, 100 rpm. Then, 1.5 mL of each bacterial culture was centrifuged (20°C, 5 min, 14,000 rpm), the supernatant was removed, and the pellet was resuspended in sterile distilled water. Then, 100 μL of the suspension were inoculated in 900 μL of YM medium with and without tryptophan (1 g/L). The outermost wells of the plate were filled with the culture medium free of bacteria as blanks. The test was performed in triplicate. Incubation was at 28°C for 72 h. The strain R-42086 (<i>Pseudomonas</i> sp.) was used as a positive control (<a href="#B26">Ghyselinck et al., 2013</a>).</p> <p class="mb0">After incubation, the plates were centrifuged at 20°C, 3,700 rpm for 5 min. Then, 50 μL of the supernatant was transferred to flat bottom 96-wells plate and 100 μL of Salkowsky’s reagent (2% 0.5 M FeCl<sub>3</sub> in 35% HClO<sub>4</sub> solution) was added and mixed by pipetting. The plate was then kept in the dark for 30 min before measuring the optical density. A calibration curve was made with 0, 0.5, 1, 2, 5, 10, 15, 20, 25, 30 μg of IAA/mL.</p> <h3>Enzymatic Activities</h3> <p class="mb0">Our isolates’ ability to recycle plant polysaccharides such as cellulose, pectin and lignin was tested through phenotypic enzymatic assays.</p> <h4>Pectinase and Cellulase Activities</h4> <p class="mb0">Depending on the objective of the test, a minimum medium (4 g/L KH<sub>2</sub>PO<sub>4</sub>, 6 g/L Na<sub>2</sub>HPO<sub>4</sub>, 2 g/L (NH<sub>4</sub>)<sub>2</sub>SO<sub>4</sub>, 1 g/L yeast extract, 0.001 g/L FeSO<sub>4</sub>, 0.2 g/L MgSO<sub>4</sub>, 0.001 g/L CaCl<sub>2</sub>, 0.00001 g/L H<sub>3</sub>BO<sub>3</sub>, 0.00001 g/L MnSO<sub>4</sub>, 0.00007 g/L ZnSO<sub>4</sub>, 0.00005 g/L CuSO<sub>4</sub>, 0.00001 g/L MoO<sub>3</sub>, 15 g/L agar, pH 7) supplemented with 5 g/L of either pectin or carboxymethyl cellulose was used for this assay. Dense bacterial suspensions were made in sterile PBS (OD 0.5–0.6). Then, 10 μL of each bacterial suspension was spotted onto the center of the plate. The test was performed in triplicates and plates were incubated at 28°C for 5 days. Plates were then checked for the presence of a solubilization halo. The halo was visualized by the addition of 0.01% congo red and 1% hexadecyltrimethylammonium bromide (CTAB) solutions for the cellulase and pectinase tests, respectively. The strain LMG 16323 (<i>Cellulomonas cellasea</i>) was used as a positive control for the cellulase assay whilst strain LMG 2404 (<i>Pectobacterium carotovorum</i> subsp. <i>carotovorum</i>) was used as a positive control for the pectinase test.</p> <h4>Ligninolytic Activity</h4> <p class="mb15">This assay was conducted in two steps: a first screening on minimum medium (4 g/L KH<sub>2</sub>PO<sub>4</sub>, 6 g/L Na<sub>2</sub>HPO<sub>4</sub>, 2 g/L (NH<sub>4</sub>)<sub>2</sub>SO<sub>4</sub>, 1 g/L yeast extract, 0.001 g/L FeSO<sub>4</sub>, 0.2 g/L MgSO<sub>4</sub>, 0.001 g/L CaCl<sub>2</sub>, 0.00001 g/L H<sub>3</sub>BO<sub>3</sub>, 0.00001 g/L MnSO<sub>4</sub>, 0.00007 g/L ZnSO<sub>4</sub>, 0.0000 5 g/L CuSO<sub>4</sub>, 0.00001 g/L MoO<sub>3</sub>, 15 g/L agar, pH 7) supplemented with 5 g/L lignin and a second test of selected bacteria on the same minimum medium with 25 mg/L of methylene blue.</p> <p class="mb15">To screen for ligninolytic activity, dense bacterial suspensions (OD 0.5–0.6) were made in sterile PBS. Then, 10 μL of each bacterial suspension was spotted onto the middle of the plate. The experiment was conducted in triplicates and the plates were incubated at 28°C for 5 days before checking for bacterial growth. Bacteria that were able to grow on lignin medium were transferred two more times to the same medium to ensure that survival was independent of the previous nutrient stock.</p> <p class="mb0">After a total of three transfers, strains that retained the ability to grow were selected to check for their ability to solubilize methylene blue. Structurally, methylene blue is very similar to lignin and both compounds can be degraded by the same enzymes. When methylene blue is degraded, it loses its color and can therefore be used to identify lignin-degrading bacteria (<a href="#B10">Bandounas et al., 2011</a>). Dense bacterial suspensions were made in sterile PBS. Then, 10 μL of each bacterial suspension was spotted onto the middle of the plate. The plates were incubated for 1 week at 28°C and growth was checked daily. Bacteria able to metabolize methylene blue are expected to produce bright halos around their colonies.</p> <h3>Susceptibility Assay</h3> <p class="mb0">Susceptibility assays were conducted to assess the sensitivity of <i>A. tinctoria</i> endophytic bacteria isolates to the antimicrobial effects of A/S derivatives. The diffusion assay using filter disks described by <a href="#B12">Bauer et al. (1966)</a> was performed. The concentration tested was 50 μg per filter disk, following <a href="#B17">Brigham et al. (1999)</a>. A mixture of alkannin/shikonin and their derivatives (A/S mixture) was isolated after extraction and further fractionation steps from <i>A. tinctoria</i> roots, as described in <a href="#B8">Assimopoulou et al. (2008)</a> and <a href="#B78">Tappeiner et al. (2013)</a>. The mixture was first solubilized in acetone to a concentration of 46.7 mg/mL and then diluted in sterile water to a concentration of 2.5 mg/mL. Then, 20 μL of each test solution were used to inoculate the filter disks. In total, six filter disks were used in this assay: three were inoculated with the A/S mixture (50 μg/filter disk), one with acetone-water solution (5.9% acetone; used as an A/S mixture solvent control), one with ampicillin (50 μg/filter disk; as a control antibiotic), and one with MilliQ water (as ampicillin solvent control). Dense bacterial suspensions were prepared in PBS and 100 μL of each suspension was inoculated by spreading on R2A plates. Individual filter disks containing 20 μL of each test solution were left to dry for 30 min before being transferred onto the plates. The test was performed in triplicate. Control strains were selected based on the results reported by <a href="#B17">Brigham et al. (1999)</a>: LMG 8224 <i>(Staphylococcus aureus</i> subsp. <i>aureus</i>) and LMG 7135 (<i>Bacillus subtilis</i> subsp. <i>subtilis</i>) as sensitive strains and LMG 8223 (<i>Escherichia coli</i>) as a resistant strain.</p> <h3>Induction of A/S Production in Hairy Roots of <i>A. tinctoria</i></h3> <p class="mb15">Hairy roots of <i>A. tinctoria</i> were produced with a modified protocol (<a href="#B17">Brigham et al., 1999</a>; <a href="#B24">Fukui et al., 1999</a>; <a href="#B35">Kim et al., 2009</a>) as follows: <i>Agrobacterium rhizogenes</i> strain LMG 149 was grown in 40 mL Nutrient Broth (Difco) medium at 28°C for 48 h in the dark and at 100 rpm agitation. The leaves of sterile <i>A. tinctoria</i> explants provided by IPBGR, HAO Demeter (Thessaloniki, Greece) were cut and inoculated at different spots with a syringe filled with a bacterial solution of <i>A. rhizogenes</i> (OD = 0.5–0.6). Each inoculated leaf was transferred onto solid Murashige and Skoog (MS, Duchefa) medium supplemented with 3% sucrose and 0.8% phytoagar (Duchefa) and kept for 1 week at 25°C in the dark until roots appeared. As a control, non-inoculated leaves were cultivated under the same conditions. Developing roots (approximately 1 cm in length), were cut off and transferred weekly (for a period of 3–4 weeks) to a new MS solid medium containing 1% sucrose, 0.8% phytoagar, and 500 mg/L of cefotaxime. The roots were then propagated in liquid MS medium supplemented with 3% sucrose (<a href="#B17">Brigham et al., 1999</a>; <a href="#B24">Fukui et al., 1999</a>; <a href="#B35">Kim et al., 2009</a>).</p> <p class="mb15">To evaluate the ability of bacteria to induce A/S production in the hairy roots of <i>A. tinctoria</i>, a first screening was performed in 6-well plates. The bacteria for this test were selected based either on their plant growth promoting properties or their enzymatic activities. Firstly, 7 mL of MS + 1% sucrose medium were added to each well, followed by the aseptic addition of young root segments. Bacteria were inoculated to a final OD of 0.001/mL. One 6-well plate was prepared per strain. In addition, an uninoculated control plate was prepared. Plates were incubated in the dark at 100 rpm agitation at 25°C for 1 week. The roots from individual wells were pooled per plate and lyophilized. The extraction of A/S was conducted overnight with 8 mg of dried roots in 250 μL of methanol and the OD was read at 520 nm (<a href="#B9">Assimopoulou et al., 2009</a>).</p> <p class="mb0">Among seven candidates showing an OD > 0.2 at 520 nm in the first screening, four were subsequently tested in a larger volume. Five 100 mL Erlenmeyer filled with 50 mL of MS + 1% sucrose medium were used per treatment. Pieces of young roots were then carefully added in each Erlenmeyer and incubated for 1 week at 25°C (100 rpm). The Erlenmeyers were then randomized before being inoculated with bacteria to a final OD of 0.001. One uninoculated control (5 replicates) was also prepared. Erlenmeyers were incubated for 1 week at 25°C (100 rpm). The roots from each Erlenmeyer were collected and lyophilized. The extraction was conducted overnight using 40 mg of dried roots in 1,250 μL of methanol. The OD was read at 520 nm and one-factor Anova followed by a Neuman-Keuls test was conducted on the results with the software R x64 3.1.0.</p> <a id="h4" name="h4"></a><h2>Results</h2> <h3 class="pt0">Isolation and Identification of Root Endophytic Bacteria</h3> <p class="mb0">For our study nine different populations of endogenous <i>Alkanna tinctoria</i> from Northern and Southern Greece have been explored. The first isolation campaign assessed the media that would allow the growth of a wide diversity of culturable bacteria and yielded 1,483 isolates. MALDI-TOF mass spectra of these isolates were compared and grouped, resulting in 914 representative strains that were selected for genotypic identification by 16S rRNA gene sequencing. This allowed identification of 142 distinct phylotypes of endophytic bacteria following the classification threshold values at genus or species level introduced by <a href="#B54">Moreira and López-García (2014)</a> and <a href="#B84">Yarza et al. (2014)</a>. The number of isolates and phylotypes recovered for each plant sample and medium is available in <a href="#S9">Supplementary Table S1</a>. The coverage of bacterial diversity for each medium tested was obtained by dividing the number of unique phylotypes from the selected medium by the total number of phylotypes. The media that yielded the highest diversity were medium 1/10 869 supplemented with 32 mM allantoin and medium 1/10 TSA (<a href="#T1">Table 1</a>). Moreover, media R2A, 1/10 869 and 1/10 869 supplemented with 0.32 mM allantoin allowed the cultivation of members of additional genera including <i>Acidovorax</i>, <i>Micromonospora</i>, <i>Kocuria</i>, <i>Diaminobutyricimonas</i>, and <i>Muciliginibacter</i> (<a href="#S9">Supplementary Figure S1</a>).</p> <div class="DottedLine"></div> <div class="Imageheaders">TABLE 1</div> <div class="FigureDesc"> <a href="https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-t001.jpg" name="table1" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-t001.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-t001.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-t001.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-t001.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-t001.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-t001.jpg" alt="www.frontiersin.org" id="T1" loading="lazy"> </picture> </a> <p><strong>Table 1.</strong> Coverage of bacterial diversity of different media, where the number of unique phylotypes in the selected medium wasdivided by the total number of detected phylotypes is given inpercentage (%).</p> </div> <div class="clear"></div> <div class="DottedLine"></div> <p class="mb15 w100pc float_left mt15">For the isolation from the second and third collection campaigns, the media R2A, 1/10 TSA, 1/10 869 and 1/10 869 + 32 mM allantoin were used to maximize the culturable diversity. Moreover, the first isolation campaign indicated that extended incubation at 20°C led to a 15.2% increase in diversity at higher dilutions. Most of these isolates were slow-growing Gram-positive bacteria including <i>Mycobacterium</i> sp., <i>Micromonospora</i> sp., <i>Lysinimonas</i> sp., and <i>Micrococcus</i> sp. Then in further isolations, the plates were incubated at 20°C for 2 weeks and colonies were picked after 1 and 2 week(s), respectively.</p> <p class="mb0">The second and third isolation campaigns using four media only yielded 770 and 582 isolates, respectively. Together with the isolates from the first campaign, this gave 2835 primary bacterial isolates in total. Protein profiles of all these isolates were compared by MALDI-TOF MS and grouped. This allowed the selection of 1,428 representative strains, 914 of which had already been identified by 16S rRNA gene sequencing in the first isolation campaign. The remaining 514 representative strains were also identified by 16S rRNA gene sequencing. In total, among the 1,428 selected representative strains, 197 unique phylotypes were recovered, belonging to 14 genera of Actinobacteria, 6 genera of Bacteroidetes, 11 genera of Firmicutes, and 44 genera of Proteobacteria. Also, three potentially new genera and 40 potentially new species were recovered from the roots of wild <i>A. tinctoria</i> plants. The bacteria were distributed in four phyla, i.e., Bacteroidetes, Proteobacteria, Actinobacteria, and Firmicutes. The plants of the third isolation campaign yielded relatively more Gram positive bacteria (Actinobacteria and Firmicutes) compared to the other plants. Similarly, the plants of the 1st and 2nd isolation campaigns yielded more Alphaproteobacteria and Gammaproteobacteria, respectively (<a href="#S9">Supplementary Figure S2</a>). Most of the isolates belonged to the Proteobacteria, particularly the Gammaproteobacteria, Alphaproteobacteria, and Betaproteobacteria. Members of the genera <i>Pseudomonas</i> were found in eight of the nine plants studied, whereas <i>Pantoea, Xanthomonas</i> and <i>Bacillus</i> were recovered from seven <i>A. tinctoria</i> plants. Additionally, representatives of <i>Stenotrophomonas</i> were found in six of the nine plants (<a href="#F1">Figure 1</a>). These genera were also isolated from all the tested media (1/10 869, 1/10 869 + 32 mM allantoin, 1/10 TSA and R2A). The isolates that were less than 94.8% similar to the type strain of any bacterial species represent four potentially new genera which are related to <i>Filimonas</i>, <i>Bordetella</i>, <i>Cohnella</i> and <i>Paenibacillus</i>. Moreover, 40 bacterial strains that were less than 98.7% similar to the type strain of any bacterial species probably represent potential new species. Of these, members of the Bacteroidetes are related to <i>Chitinophaga</i>, <i>Flavobacterium</i>, <i>Mucilaginibacter</i>, and <i>Pedobacter</i>. Potentially new species within the Phylum Firmicutes are related to <i>Bacillus</i>, <i>Cohnella</i>, <i>Domibacillus</i>, <i>Paenibacillus</i>, and <i>Tumebacillus</i>. Potentially new Proteobacteria isolates are related to <i>Acinetobacter</i>, <i>Allorhizobium</i>, <i>Beijerinckia</i>, <i>Bradyrhizobium</i>, <i>Brevundimonas</i>, <i>Janthinobacterium</i>, <i>Massilia</i>, <i>Ochrobactrum</i>, <i>Pseudomonas</i>, <i>Roseomonas</i>, <i>Rhizobium</i>, <i>Rhizorhapis</i>, <i>Shinella</i>, <i>Sphingobium</i>, <i>Sphingomonas</i>, and <i>Stenotrophomonas</i>. Finally, potentially new isolated Actinobacteria members are related to the genera <i>Cellulomas</i>, <i>Conexibacter</i>, <i>Diaminobutyricimonas</i>, <i>Lysinimonas</i>, <i>Mycobacterium</i>, and <i>Nocardioide</i>s.</p> <div class="DottedLine"></div> <div class="Imageheaders">FIGURE 1</div> <div class="FigureDesc"> <a href="https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-g001.jpg" name="figure1" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-g001.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-g001.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-g001.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-g001.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-g001.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-g001.jpg" alt="www.frontiersin.org" id="F1" loading="lazy"> </picture> </a> <p><strong>Figure 1.</strong> Diversity of genera isolated from wild-growing <i>Alkanna tinctoria</i> plants and the number of plant individuals in which they were found. The number of species found per genus is specified in parentheses. Different colors correspond to specific bacterial phyla or classes.</p> </div> <div class="clear"></div> <div class="DottedLine"></div> <h3>Plant Growth-Promoting Activity</h3> <p class="mb0">One hundred and twenty-seven strains which represented most of the bacterial diversity recovered, were tested for their plant growth promoting activity <i>in vitro</i>. The results are summarized in <a href="#F2">Figure 2</a> (additional information is provided in the <a href="#S9">Supplementary Table S2</a>). The strains expressing positive activity for all four tested parameters belonged to the genera <i>Pseudomonas</i> and <i>Bacillus</i>. The ones expressing positive activity for at least three of the parameters tested belonged to the genera <i>Pseudomonas</i>, <i>Pantoea</i>, <i>Inquilinus</i>, <i>Rhizobium</i>, and <i>Bacillus</i>. On the other hand, bacteria from the genus <i>Stenotrophomonas</i> seem to only be able to produce siderophores. The partial 16S sequences of these 127 tested strains are available in GenBank database under the accession numbers MW353471–MW353597 (<a href="#S9">Supplementary Table S3</a>).</p> <div class="DottedLine"></div> <div class="Imageheaders">FIGURE 2</div> <div class="FigureDesc"> <a href="https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-g002.jpg" name="figure2" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-g002.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-g002.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-g002.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-g002.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-g002.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-g002.jpg" alt="www.frontiersin.org" id="F2" loading="lazy"> </picture> </a> <p><strong>Figure 2.</strong> Neighbor-joining phylogenetic tree based on 16S rRNA gene sequences, with Juke-Cantor model, showing the phylogenetic relationships of strains tested <i>in vitro</i> for plant growth, cell-wall degrading enzymes and susceptibility to the mixture of A/S. Activities detected are shown in the outer circle. Sequences were aligned using 361 CLC Main Workbench 7.9.1 (Qiagen). Subsequently, a phylogenetic maximum-likelihood tree (1000 bootstraps) was reconstructed and visualized using the iTOL software 5.6.3 (<a href="#B43">Letunic and Bork, 2019</a>).</p> </div> <div class="clear"></div> <div class="DottedLine"></div> <h3>Enzymatic Activities</h3> <p class="mb0">Enzymatic activities of the 127 strains are presented in <a href="#F2">Figure 2</a> (additional information is provided in <a href="#S9">Supplementary Table S2</a>). The cellulase activity seemed to be predominant in the <i>Rhizobiaceae</i> family, whereas pectinase activity was abundant among the Bacteroidetes phylum. Among the strains tested, some showed two degrading activities: pectinase and ligninolytic activities were detected for R-72191 (<i>Olivibacter</i> sp.), R-72210 (<i>Pseudomonas</i> sp.), R-72249 (<i>Pedobacter</i> sp.), R-72394 (<i>Pantoea</i> sp.), R-72464 (<i>Xanthomonas</i> sp.), R-7264, and R-74277 (<i>Bacillus</i> sp.); cellulase and pectinase activities for the strain R-71830 (<i>Brevibacillus</i> sp.) and cellulase and ligninolytic activities for R-72157 (<i>Rhizorhapis</i> sp.).</p> <h3>Susceptibility Assay</h3> <p class="mb0">Susceptibility to the antimicrobial activity of alkannin and shikonin derivatives (in the form of a mixture of A/S pigments) was studied for the 127 strains tested for PGP and enzymatic activities. A strain was considered as sensitive to A/S derivatives when an inhibition zone of more than 1 mm was observed. An example of the assay is shown in <a href="#F3">Figure 3</a>. A pattern could be observed in the susceptibility to the A/S mixture (50 μg): all Gram-positive bacteria tested were sensitive whereas the Gram-negative bacteria tested were resistant (<a href="#F2">Figure 2</a>). No such pattern was observed for ampicillin which was used as a control. As shown in <a href="#F3">Figure 3</a>, the halos observed as a result of sensitivity to A/S derivatives were always smaller in diameter than those produced as a result of ampicillin sensitivity.</p> <div class="DottedLine"></div> <div class="Imageheaders">FIGURE 3</div> <div class="FigureDesc"> <a href="https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-g003.jpg" name="figure3" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-g003.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-g003.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-g003.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-g003.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-g003.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-g003.jpg" alt="www.frontiersin.org" id="F3" loading="lazy"> </picture> </a> <p><strong>Figure 3.</strong> Susceptibility of strain R-72492 (<i>Bacillus</i> sp.) to the mixture of alkannin/shikonin derivatives isolated from <i>Alkanna tinctoria</i> roots.</p> </div> <div class="clear"></div> <div class="DottedLine"></div> <h3>Induction of A/S Derivatives in Hairy Roots of <i>A. tinctoria</i></h3> <p class="mb0">In the first screening, treatments with the following bacteria resulted in hairy root extracts showing an OD higher than the control: R-71971 (<i>Brevibacillus</i> sp.), R-72060 (<i>Variovorax</i> sp.), R-72149 (<i>Filimonas</i> sp.), R-72379 (<i>Allorhizobium</i> sp.), R-72395 (<i>Duganella</i> sp.), R-72401 (<i>Shinella</i> sp.), R-72406 (<i>Stenotrophomonas</i> sp.), R-73072 (<i>Chitinophaga</i> sp.), R-74161 (<i>Acinetobacter</i> sp.), and R-75348 (<i>Micromonospora</i> sp.) (<a href="#T2">Table 2</a>). The seven bacteria resulting in an OD > 0.20 were repeated in five replicates in a second assay. The one-factor ANOVA conducted on the results of the second assay showed that the <i>p</i>-value = 0.00179 was lower than 0.05. The bacterial treatment had an influence on the A/S content. The comparison made with the test of Newman Keuls are presented <a href="#T3">Table 3</a>. <i>Chitinophaga</i> sp. strain R-73072, <i>Allorhizobium</i> sp. strain R-72379, <i>Massilia</i> sp. strain R-72395, and <i>Micromonospora</i> sp. strain R-75348 induced significantly more A/S derivatives in the hairy roots of <i>A. tinctoria</i> when compared to the uninoculated control.</p> <div class="DottedLine"></div> <div class="Imageheaders">TABLE 2</div> <div class="FigureDesc"> <a href="https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-t002.jpg" name="table2" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-t002.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-t002.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-t002.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-t002.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-t002.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-t002.jpg" alt="www.frontiersin.org" id="T2" loading="lazy"> </picture> </a> <p><strong>Table 2.</strong> Optical density at 520 nm reflecting the total A/S content of hairy roots extracts of <i>Alkanna tinctoria</i> treated with selected bacteria.</p> </div> <div class="clear"></div> <div class="DottedLine mb15"></div> <div class="Imageheaders">TABLE 3</div> <div class="FigureDesc"> <a href="https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-t003.jpg" name="table3" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-t003.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-t003.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-t003.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-t003.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-t003.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/633488/fmicb-12-633488-HTML/image_m/fmicb-12-633488-t003.jpg" alt="www.frontiersin.org" id="T3" loading="lazy"> </picture> </a> <p><strong>Table 3.</strong> Comparisons of the OD 520 nm reflecting the total A/S content of hairy roots extracts of <i>Alkanna tinctoria</i> inoculated with the best bacterial candidates with Neuman Keuls test.</p> </div> <div class="clear"></div> <div class="DottedLine"></div> <a id="h5" name="h5"></a><h2>Discussion</h2> <p class="mb15">The cultivation of members of <i>Boraginaceae</i> with strong medicinal value such as <i>A. tinctoria</i> and <i>Lithospermum</i> spp. has proven to be difficult. For example, <i>Lithospermum</i> spp. germinate poorly and seedlings are highly susceptible to viral infections. Additionally, plants can only be harvested 2–3 years after germination and the in-field maintenance of these plants has also proved to be difficult (<a href="#B85">Yazaki, 2017</a>). Applying suitable endophytes to facilitate plant growth by increasing the plant biomass and/or by inducing A/S production can be a sustainable approach toward increasing plant yield and production of these valuable compounds.</p> <p class="mb15">As a first step toward the elucidation of the potential role of root endophytic bacteria in the production for secondary metabolites such as A/S derivatives of <i>A. tinctoria</i>, we isolated and characterized culturable endophytic bacteria from <i>A. tinctoria</i> roots. In total, 197 unique phylotypes were recovered, representing 4 phyla. Also, three potentially new genera and 40 potentially new species were recovered from the roots of wild <i>A. tinctoria</i> plants. Most studies to date involving the isolation of endophytic bacteria typically use one type of isolation medium to cultivate a wide range of microorganisms (e.g., nutrient agar or TSA), a set temperature of 28°C and an incubation time between 48 and 72 h (<a href="#B25">Germida et al., 1998</a>; <a href="#B50">Mbai et al., 2013</a>; <a href="#B4">Anjum and Chandra, 2015</a>; <a href="#B70">Saini et al., 2015</a>). In this study, we showed that a higher diversity of bacteria can be obtained when more than one medium is used. Nutrient-poor media such as R2A or diluted TSA seem better at capturing more diversity than a rich medium such as ISP2 (<a href="#T1">Table 1</a> and <a href="#S9">Supplementary Figure S1</a>). The latter is a medium rich in nitrogen and carbon sources and has been designed for the routine cultivation of <i>Streptomyces</i> sp. (<a href="#B74">Shirling and Gottlieb, 1966</a>). However, as it may favor the fast-growing bacteria, it may be less suitable to isolate slow growing ones. R2A medium was designed for slow-growing bacteria (<a href="#B68">Reasoner and Geldreich, 1985</a>) and medium 1/10 869 for endophytes (<a href="#B22">Eevers et al., 2015</a>), whereas TSA medium is non-selective and allows the growth of a wide range of microorganisms (<a href="#B42">Leavitt et al., 1958</a>). The dilution of TSA increased the growth of slow-growing bacteria when compared to the non-diluted medium. Changes in the quantity and the quality of the carbon source and the nature of electrons donors (e.g., succinate, butyrate, acetate) and acceptors (HEPES solution; <a href="#B38">Köpke et al., 2005</a>), as well as the addition of supplements like enzymes or antibiotics to isolation media are known to generate higher microbial diversity (<a href="#B3">Alain and Querellou, 2009</a>). For example, the nitrogen sources of TSA medium are casein and peptones whereas R2A and 869 media contain yeast extract. Moreover, TSA does not have additional carbon sources such as glucose. Poor media limit the risk that fast-growing bacteria eliminate those that grow slower by outcompeting them for nutrients or by negatively affecting the growth conditions (pH or the production of metabolites). Critically, slow-growers or species that grow poorly <i>in vitro</i> may be naturally abundant in planta (<a href="#B3">Alain and Querellou, 2009</a>; <a href="#B39">Kram and Finkel, 2015</a>). Lower temperature and longer incubation time were also more suited to recovering gram-positive bacteria such as Actinobacteria. Indeed, studies focusing on Actinobacteria demonstrated that an incubation period of 3–4 weeks was necessary for their isolation (<a href="#B6">Araújo et al., 2000</a>; <a href="#B19">Coombs and Franco, 2003</a>; <a href="#B51">Misk and Franco, 2011</a>).</p> <p class="mb15">While the isolation conditions are important determining factors for the recovery of bacterial isolates, the diversity observed here between different roots (<a href="#F1">Figure 1</a> and <a href="#S9">Supplementary Figure S2</a>) indicates that other factors are also important. For example, no Gammaproteobacteria such as <i>Pseudomonas</i> sp., <i>Xanthomonas</i> sp., or <i>Pantoea</i> sp. seemed to be present in one of the root samples (<a href="#F1">Figure 1</a>). Bacterial isolation results can be biased by the origin and storage conditions of the biological sample or the colony picking method, in addition to the isolation conditions, which may have contributed to the variation in phylotype distribution observed between roots and isolation campaigns (<a href="#S9">Supplementary Figure S2</a>). We studied wild-collected plants from different locations and therefore, parameters such as the genetics of the plant (<a href="#B28">Haney et al., 2015</a>), local soil composition (<a href="#B44">Liu et al., 2019</a>), or the presence of neighboring plants (<a href="#B72">Schlatter et al., 2015</a>; <a href="#B23">Essarioui et al., 2016</a>) might also influence the diversity of bacteria recovered. Microbiome analysis as well as the study of the growth conditions of the plant in its natural environment might shed light on bacterial variation between samples.</p> <p class="mb15">The endophytic bacteria found in most of the root samples were tested for a number of plant-growth promotion (PGP) characteristics. The most interesting species for plant growth promoting activity belong to the genera <i>Pseudomonas</i>, <i>Pantoea</i>, <i>Inquilinu</i>s, <i>Rhizobium</i>, and <i>Bacillus</i> (<a href="#F2">Figure 2</a>, <a href="#S9">Supplementary Table S2</a>). Members of these genera were recovered on all media used for isolation. The ability to grow easily <i>in vitro</i> is promising for their application as plant growth promoting rhizobacteria (PGPRs). Some bacteria showed variable results were obtained from the ACC deaminase test (<a href="#S9">Supplementary Table S2</a>). These bacteria were colored and/or were prone to form biofilms or clumps which can lead inaccurate spectrophotometric readings. To overcome this issue, quantitative analysis might be applied by measuring the amount of α-ketobutyrate at 540 nm (<a href="#B63">Penrose and Glick, 2003</a>).</p> <p class="mb15">Moreover, several bacteria produced <i>in vitro</i> cell-wall degrading enzymes such as cellulases, pectinases and ligninases. These properties facilitate bacterial entry and spread within the plant tissues and may contribute to the endophytic lifestyle of these bacteria. Strains belonging to <i>Pseudomonas</i> sp., <i>Pantoea</i> sp., <i>Rhizobium</i> sp., and <i>Bacillus</i> sp. expressing PGP and enzymatic activities (<a href="#F2">Figure 2</a> and <a href="#S9">Supplementary Table S2</a>) might thus show stronger impact on plant growth or A/S induction due to their ability to actively colonize the plant.</p> <p class="mb15">The resistance assay demonstrated that Gram-negative bacteria are resistant to the antimicrobial properties of A/S derivatives (<a href="#F2">Figure 2</a> and <a href="#S9">Supplementary Table S2</a>). Although the activity of A/S derivatives at 50 μg seemed weak, the experiment confirmed the antimicrobial properties of these naphthoquinones. The antimicrobial activity of A/S has been linked to their ability to form semiquinone radicals by interacting with reactive oxygen species. They can generate endogenous superoxide anion radicals, resulting in their cytotoxicity (<a href="#B60">Papageorgiou et al., 2008</a>, <a href="#B61">1999</a>; <a href="#B57">Ordoudi et al., 2011</a>). The peptidoglycan cell wall of the Gram-positive bacteria is permeable to molecules with molecular weights in the range of 30,000–57,000 Da, and hence allows for the entry of many small antimicrobials which may partially explain their sensitivity (<a href="#B41">Lambert, 2002</a>). On the other hand, several mechanisms might be involved in the resistance of the Gram-negative bacteria to A/S, especially through redox processes. Chemical and transcriptomic analyses may provide a better understanding of the processes involved. Most of the bacteria having a positive effect in the <i>in vitro</i> plant growth promoting activities tested were Gram-negative and thus resistant to A/S derivatives. This resistance may provide a competitive advantage for colonizing the plant and living in the root tissues. Consequently, the plant may select for plant growth promoting bacteria through the production of A/S derivatives. Alternatively, sensitive bacteria may colonize the plant shortly after germination when the A/S derivatives content is low or they may be present in the seed and are vertically transmitted (<a href="#B81">Truyens et al., 2014</a>). In the future, these hypotheses might be tested by inoculating isolates that are sensitive to A/S at different plant growth stages and by tracking their presence and abundance within the plant, thus establishing whether or not these strains can colonize and survive in the plant or not.</p> <p class="mb15">Studies have shown that in the hairy roots of <i>A. tinctoria</i>, A/S derivatives are produced by root border cells of the growing root tips. They are then sequestered as lipid granules in the phospholipid layer of these cells and accumulate in apoplastic spaces. However, how the A/S derivatives are secreted into the environment still remains unclear. Nevertheless, it is known that this process results from plant stress and involves the actin filaments (<a href="#B17">Brigham et al., 1999</a>; <a href="#B79">Tatsumi et al., 2016</a>). Depending on where the bacteria colonize the plant, it is possible that they do not come into contact with A/S derivatives. Colonization assays can provide insights into the relationship between plant individuals and bacteria in the presence of alkannins and shikonins. Moreover, it has been shown that ethylene regulates the colonization of plant tissue by bacteria: the absence of ethylene in a plant or the addition of an ethylene inhibitor leads to a higher degree of colonization. Bacteria that are able to affect the ethylene level are more competent at colonizing plants (<a href="#B29">Hardoim et al., 2008</a>; <a href="#B45">Liu et al., 2017</a>). The modulation of plant ethylene levels by bacteria can occur by cleavage of 1-aminocyclopropane-1-carboxylate (ACC), a precursor of ethylene or by inhibiting ACC synthase and/or β-cystathionase, both being enzymes involved in the ethylene biosynthesis pathway (<a href="#B29">Hardoim et al., 2008</a>; <a href="#B45">Liu et al., 2017</a>). To confirm whether bacteria can effectively colonize and positively affect the plant growth and the total A/S content, in planta tests must be performed.</p> <p class="mb15"><i>Chitinophaga</i> sp. strain R-73072, <i>Allorhizobium</i> sp. strain R-72379, <i>Massilia</i> sp. strain R-72395, and <i>Micromonospora</i> sp. strain R-75348 showed the ability to directly induce A/S production in <i>A. tinctoria</i> hairy root cultures. Hairy roots are genetically modified plant material (<a href="#B27">Gutierrez-Valdes et al., 2020</a>). The use of MS + 1% sucrose medium, which is a poor medium for bacterial culture, as well as the presence of agitation, might affect the ability of the bacteria to colonize the roots or their abilities to produce biofilm and/or metabolites. During plant colonization, the production of bacterial enzymes or metabolites may induce the production of A/S derivatives by the plant. Our hairy root system served as a general screening tool and may be not optimized for specific plant-bacteria interactions. It might therefore underestimate the number of A/S inducers. Nonetheless, <i>in vitro</i> whole plant systems usually employ growth medium similar to MS (<a href="#B64">Phillips and Garda, 2019</a>) and therefore bacteria showing inducing properties in hairy roots can likely induce A/S <i>in vitro</i> plant system. The bacterial strains R-73072, R-72379, and R-72395 inducing A/S in our system, expressed cell-wall degrading enzymatic activities (pectinase or ligninase) <i>in vitro</i>. Competent endophytes are able to release cell wall degrading enzymes such as cellulases, xylanases, pectinases, and endoglucanases, which facilitate bacterial entry and spread within the plant tissues (<a href="#B34">Kandel et al., 2017</a>; <a href="#B65">Pinski et al., 2019</a>). Nonetheless, colonization remains an invasive process and thus might induce plant defense response, resulting in the synthesis of plant antimicrobials. Alkannin and shikonin derivatives show antimicrobial activities and can thus be considered as plant defense compounds.</p> <p class="mb15">Although R-75348 did not show any cell-wall degrading activities <i>in vitro</i>, several studies have demonstrated that <i>Micromonospora</i> species do have a role in the breakdown of plant cell walls through the production of hydrolytic enzymes (<a href="#B30">Hirsch and Valdés, 2010</a>; <a href="#B80">Trujillo et al., 2015</a>). Our test conditions may not have been suitable for this strain. Alternatively, genome analysis might reveal the presence of such enzymes. Moreover, <i>Micromonospora</i> sp. is also known to produce antibiotics (<a href="#B15">Boumehira et al., 2016</a>). Inducing the production of A/S derivatives may depend on plant-bacteria communication through such metabolites. Indeed, some molecules are described as antibiotics because of their effect on microorganisms under <i>in vitro</i> conditions although their function in the natural habitat can be different. Such molecules can play a role in plant-microbe interactions but can also act as Microbe-Associated Molecular Patterns (MAMPs). MAMPs are resistance-inducing stimuli recognized by specific plant receptors (<a href="#B37">Köhl et al., 2019</a>). They can also induce pathways involved in plant defense responses.</p> <p class="mb15">We hypothesize that the endophyte’s production of cell-wall degrading enzymes and/or secondary metabolites during plant colonization may cause a plant stress resulting in the production of alkannin and shikonin derivatives.</p> <p class="mb0">This study demonstrated the importance of the isolation conditions for the diversity of endophytic isolates recovered from plant roots of <i>A. tinctoria</i>. Nutrient-poor isolation media coupled with an incubation temperature of 20°C and an incubation period of a minimum of 2 weeks allowed for a recovery of a high diversity of culturable endophytic bacteria from <i>A. tinctoria</i>. Although these findings should be validated in greenhouse or field conditions, the positive <i>in vitro</i> results found regarding potential plant growth promotion features suggest that some of these bacteria might be valuable for future in planta applications. These can be of agronomical interest to boost biomass production or crop yield. Such endophytes also have the potential to increase the yield of secondary metabolites such as A/S derivatives from these medicinal plants by increasing the total biomass. As demonstrated in our study, certain endophytes can also induce A/S production in the roots, probably through to the recognition of bacteria by the plant. These findings open-up the perspective of using a combination of endophytes with the potential for plant growth promotion and induction of secondary metabolite production as a sustainable approach toward increasing the production of secondary metabolites in selected medicinal plants.</p> <a id="h6" name="h6"></a><h2>Data Availability Statement</h2> <p class="mb0">The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/<a href="#S9">Supplementary Material</a>.</p> <a id="h7" name="h7"></a><h2>Author Contributions</h2> <p class="mb0">AW, CS, AAs, and NF designed the study and secured the funding. AR, HN, and AAl designed and performed the experiments. AR analyzed the data and wrote the manuscript. All authors edited, proofread, and approved the manuscript.</p> <a id="fun1" name="fun1"></a><h2>Funding</h2> <p class="mb0">This project (Micrometabolite) has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie grant agreement no. 721635.</p> <a id="conf1" name="conf1"></a><h2>Conflict of Interest</h2> <p class="mb0">The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p> <a id="ack1" name="ack1"></a><h2>Acknowledgments</h2> <p class="mb0">We would like to thank our colleague Stephanie Fordeyn for language advise and proofreading of the manuscript.</p> <a id="S9" name="S9"></a><h2>Supplementary Material</h2> <p class="mb0">The Supplementary Material for this article can be found online at: <a href="https://www.frontiersin.org/articles/10.3389/fmicb.2021.633488/full#supplementary-material">https://www.frontiersin.org/articles/10.3389/fmicb.2021.633488/full#supplementary-material</a></p> <a id="refer1" name="refer1"></a><h2>References</h2> <div class="References" style="margin-bottom:0.5em;"> <p class="ReferencesCopy1"><a name="B1" id="B1"></a>Abd_Allah, E. 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Microbiol.</i> 12:633488. doi: 10.3389/fmicb.2021.633488</p> <p id="timestamps"> <span>Received:</span> 25 November 2020; <span>Accepted:</span> 13 January 2021;<br><span>Published:</span> 03 February 2021.</p> <div> <p>Edited by:</p> <a href="https://loop.frontiersin.org/people/476457/overview">Aleksa Obradović</a>, University of Belgrade, Serbia</div> <div> <p>Reviewed by:</p> <a href="https://loop.frontiersin.org/people/360397/overview">Carolina Chiellini</a>, Italian National Research Council, Italy<br> <a href="https://loop.frontiersin.org/people/549870/overview">Debdulal Banerjee</a>, Vidyasagar University, India</div> <p><span>Copyright</span> © 2021 Rat, Naranjo, Krigas, Grigoriadou, Maloupa, Alonso, Schneider, Papageorgiou, Assimopoulou, Tsafantakis, Fokialakis and Willems. This is an open-access article distributed under the terms of the <a rel="license" href="http://creativecommons.org/licenses/by/4.0/" target="_blank">Creative Commons Attribution License (CC BY)</a>. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p> <p><span>*Correspondence:</span> Angélique Rat, <a id="encmail">YW5nZWxpcXVlLnJhdEB1Z2VudC5iZQ==</a></p> <div class="clear"></div> </div></div></div> <p class="AbstractSummary__disclaimer"><span>Disclaimer: </span> All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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Indexed in PubMed Central (PMC), Scopus and the DOAJ, the journal explores the habitable world and the potential of microbial life.\u003C\u002Fp\u003E\n\n\u003Cp\u003ELed by Field Chief Editor Prof Paul D. Cotter (Co-founder and CTO of SeqBiome; Senior Principal Research Office, Teagasc Food Research Centre), this multidisciplinary journal welcomes submissions across the entire spectrum of microbiology and advances our understanding of the role microbes play in human lives, from health care to climate change.\u003C\u002Fp\u003E\n\n\u003Cp\u003ETopics include, but are not limited to:\u003C\u002Fp\u003E\n\n\u003Cul\u003E\n \u003Cli\u003Eancient DNA and forensic microbiology\u003C\u002Fli\u003E\n \u003Cli\u003Eantimicrobials, resistance and chemotherapy\u003C\u002Fli\u003E\n \u003Cli\u003Eaquatic microbiology\u003C\u002Fli\u003E\n \u003Cli\u003Ebiology of archaea\u003C\u002Fli\u003E\n \u003Cli\u003Eextreme microbiology\u003C\u002Fli\u003E\n \u003Cli\u003Efood microbiology\u003C\u002Fli\u003E\n \u003Cli\u003Einfectious agents and disease\u003C\u002Fli\u003E\n \u003Cli\u003Emicrobe and virus interactions with plants\u003C\u002Fli\u003E\n \u003Cli\u003Emicrobial physiology and metabolism\u003C\u002Fli\u003E\n \u003Cli\u003Emicrobial symbioses\u003C\u002Fli\u003E\n \u003Cli\u003Emicrobiological chemistry and geomicrobiology\u003C\u002Fli\u003E\n \u003Cli\u003Emicrobiotechnology\u003C\u002Fli\u003E\n \u003Cli\u003Emicroorganisms in vertebrate digestive systems\u003C\u002Fli\u003E\n \u003Cli\u003Ephage biology\u003C\u002Fli\u003E\n \u003Cli\u003Esystems microbiology\u003C\u002Fli\u003E\n \u003Cli\u003Eterrestrial microbiology\u003C\u002Fli\u003E\n \u003Cli\u003Evirology.\u003C\u002Fli\u003E\n\u003C\u002Ful\u003E\n\n\u003Cp\u003EManuscripts that focus solely on clinical aspects of diseases, such as treatment outcomes, clinical trials, patient management, and epidemiological studies, are not suitable for publication in this journal. Additionally, studies that are purely descriptive, such as the characterization of bacterial isolates or the description of new methods, without providing significant biological insights, are not within the scope of this journal.\u003C\u002Fp\u003E\n\n\u003Cp\u003EFrontiers in Microbiology is committed to advancing developments in microorganism interactions by allowing unrestricted access to articles and communicating scientific knowledge to researchers and the public alike, to enable the scientific breakthroughs of the future.\u003C\u002Fp\u003E",palette:"cyan",impactFactor:"5.2",citeScore:"7.8",citations:"761000",showTagline:f,twitter:"@FrontMicrobiol",__typename:"Journal"},currentFrontiersJournal:{id:t,name:q,slug:u,printISSN:f,shortName:F,electronicISSN:G,abbreviation:Z,specialtyId:f,publicationDate:f,isOnline:h,isOpenForSubmissions:h,spaceId:c,field:{id:_,domainId:c,__typename:$},__typename:a},articleHubSlug:e,articleHubPage:H,currentArticle:{id:633488,doi:aa,title:ab,acceptanceDate:new Date(1610530106000),receptionDate:new Date(1606305739000),publicationDate:new Date(1612310400000),isPublished:h,abstract:ac,researchTopic:f,articleType:{id:24,name:"Original Research"},stage:{id:I,name:e},keywords:["Endophytes","Isolation","Alkanna tinctoria","Alkannin","Shikonin","hairy roots (Min5- Max 8)"],authors:[{id:ad,firstName:ae,lastName:"Rat",givenNames:ae,isCorresponding:j,isProfilePublic:h,userId:ad,affiliations:[{organizationName:J,countryName:K,cityName:e,stateName:e,zipCode:e}]},{id:af,firstName:ag,lastName:"Naranjo",givenNames:ag,isCorresponding:j,isProfilePublic:h,userId:af,affiliations:[{organizationName:J,countryName:K,cityName:e,stateName:e,zipCode:e}]},{id:ah,firstName:ai,lastName:"Krigas",givenNames:ai,isCorresponding:j,isProfilePublic:h,userId:ah,affiliations:[{organizationName:L,countryName:p,cityName:e,stateName:e,zipCode:e}]},{id:o,firstName:aj,lastName:"Grigoriadou",givenNames:aj,isCorresponding:j,isProfilePublic:j,userId:o,affiliations:[{organizationName:L,countryName:p,cityName:e,stateName:e,zipCode:e}]},{id:ak,firstName:al,lastName:"Maloupa",givenNames:al,isCorresponding:j,isProfilePublic:h,userId:ak,affiliations:[{organizationName:L,countryName:p,cityName:e,stateName:e,zipCode:e}]},{id:am,firstName:an,lastName:"Alonso",givenNames:an,isCorresponding:j,isProfilePublic:h,userId:am,affiliations:[{organizationName:ao,countryName:ap,cityName:e,stateName:e,zipCode:e}]},{id:aq,firstName:ar,lastName:"Schneider",givenNames:ar,isCorresponding:j,isProfilePublic:h,userId:aq,affiliations:[{organizationName:ao,countryName:ap,cityName:e,stateName:e,zipCode:e}]},{id:o,firstName:as,lastName:"Papageorgiou",givenNames:as,isCorresponding:j,isProfilePublic:j,userId:o,affiliations:[{organizationName:at,countryName:p,cityName:e,stateName:e,zipCode:e}]},{id:au,firstName:av,lastName:"Assimopoulou",givenNames:av,isCorresponding:j,isProfilePublic:h,userId:au,affiliations:[{organizationName:at,countryName:p,cityName:e,stateName:e,zipCode:e}]},{id:o,firstName:aw,lastName:"Tsafantakis",givenNames:aw,isCorresponding:j,isProfilePublic:j,userId:o,affiliations:[{organizationName:ax,countryName:p,cityName:e,stateName:e,zipCode:e}]},{id:ay,firstName:az,lastName:"Fokialakis",givenNames:az,isCorresponding:j,isProfilePublic:h,userId:ay,affiliations:[{organizationName:ax,countryName:p,cityName:e,stateName:e,zipCode:e}]},{id:aA,firstName:aB,lastName:"Willems",givenNames:aB,isCorresponding:j,isProfilePublic:h,userId:aA,affiliations:[{organizationName:J,countryName:K,cityName:e,stateName:e,zipCode:e}]}],editors:[{id:aC,firstName:aD,lastName:"Obradovi膰",givenNames:aD,isCorresponding:j,isProfilePublic:h,userId:aC,affiliations:[{organizationName:"Faculty of Agriculture, University of Belgrade",countryName:"Serbia",cityName:e,stateName:e,zipCode:e}]}],reviewers:[{id:aE,firstName:aF,lastName:"Chiellini",givenNames:aF,isCorresponding:j,isProfilePublic:h,userId:aE,affiliations:[{organizationName:"Pisa Research Area, National Research Council (CNR)",countryName:"Italy",cityName:e,stateName:e,zipCode:e}]},{id:aG,firstName:aH,lastName:"Banerjee",givenNames:aH,isCorresponding:j,isProfilePublic:h,userId:aG,affiliations:[{organizationName:"Vidyasagar University",countryName:"India",cityName:e,stateName:e,zipCode:e}]}],journal:{id:t,slug:u,name:q,shortName:F,electronicISSN:G,field:{id:_,domainId:c,__typename:$},specialtyId:f,journalSectionPaths:[{section:aI,__typename:"journal_journalSectionPath"}],__typename:a},section:aI,impactMetrics:{views:19499,downloads:3804,citations:59},volume:M,articleVolume:"Volume 12 - 2021",relatedArticles:[],isPublishedV2:j,contents:{fullTextHtml:"\u003Cdiv class=\"JournalAbstract\"\u003E\r\n\u003Ca id=\"h1\" name=\"h1\"\u003E\u003C\u002Fa\u003E\u003Ch1\u003EEndophytic Bacteria From the Roots of the Medicinal Plant \u003Ci\u003EAlkanna tinctoria\u003C\u002Fi\u003E Tausch (\u003Ci\u003EBoraginaceae\u003C\u002Fi\u003E): Exploration of Plant Growth Promoting Properties and Potential Role in the Production of Plant Secondary Metabolites\u003C\u002Fh1\u003E\r\n\u003Cdiv class=\"authors\"\u003E\r\n\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Fpeople\u002Fu\u002F1152558\" class=\"user-id-1152558\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F1152558\u002F24\" onerror=\"this.src='http:\u002F\u002F3b76aaf63d1816bb57bf-a34624e694c43cdf8b40aa048a644ca4.r96.cf2.rackcdn.com\u002FDesign\u002FImages\u002Fnewprofile_default_profileimage_new.jpg'\" alt=\"\"\u002F\u003EAngélique Rat\u003C\u002Fa\u003E\u003Csup\u003E1*\u003C\u002Fsup\u003E, \u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Fpeople\u002Fu\u002F1153085\" class=\"user-id-1153085\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F1153085\u002F24\" onerror=\"this.src='http:\u002F\u002F3b76aaf63d1816bb57bf-a34624e694c43cdf8b40aa048a644ca4.r96.cf2.rackcdn.com\u002FDesign\u002FImages\u002Fnewprofile_default_profileimage_new.jpg'\" alt=\"\"\u002F\u003EHenry D. Naranjo\u003C\u002Fa\u003E\u003Csup\u003E1\u003C\u002Fsup\u003E, \u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Fpeople\u002Fu\u002F389080\" class=\"user-id-389080\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F389080\u002F24\" onerror=\"this.src='http:\u002F\u002F3b76aaf63d1816bb57bf-a34624e694c43cdf8b40aa048a644ca4.r96.cf2.rackcdn.com\u002FDesign\u002FImages\u002Fnewprofile_default_profileimage_new.jpg'\" alt=\"\"\u002F\u003ENikos Krigas\u003C\u002Fa\u003E\u003Csup\u003E2\u003C\u002Fsup\u003E, \u003Cimg class=\"pr5\" src=\"http:\u002F\u002F3b76aaf63d1816bb57bf-a34624e694c43cdf8b40aa048a644ca4.r96.cf2.rackcdn.com\u002FDesign\u002FImages\u002Fnewprofile_default_profileimage_new.jpg\" alt=\"\"\u002F\u003EKaterina Grigoriadou\u003Csup\u003E2\u003C\u002Fsup\u003E, \u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Fpeople\u002Fu\u002F1178870\" class=\"user-id-1178870\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F1178870\u002F24\" onerror=\"this.src='http:\u002F\u002F3b76aaf63d1816bb57bf-a34624e694c43cdf8b40aa048a644ca4.r96.cf2.rackcdn.com\u002FDesign\u002FImages\u002Fnewprofile_default_profileimage_new.jpg'\" alt=\"\"\u002F\u003EEleni Maloupa\u003C\u002Fa\u003E\u003Csup\u003E2\u003C\u002Fsup\u003E, \u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Fpeople\u002Fu\u002F1205578\" class=\"user-id-1205578\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F1205578\u002F24\" onerror=\"this.src='http:\u002F\u002F3b76aaf63d1816bb57bf-a34624e694c43cdf8b40aa048a644ca4.r96.cf2.rackcdn.com\u002FDesign\u002FImages\u002Fnewprofile_default_profileimage_new.jpg'\" alt=\"\"\u002F\u003EAlicia Varela Alonso\u003C\u002Fa\u003E\u003Csup\u003E3\u003C\u002Fsup\u003E, \u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Fpeople\u002Fu\u002F76144\" class=\"user-id-76144\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F76144\u002F24\" onerror=\"this.src='http:\u002F\u002F3b76aaf63d1816bb57bf-a34624e694c43cdf8b40aa048a644ca4.r96.cf2.rackcdn.com\u002FDesign\u002FImages\u002Fnewprofile_default_profileimage_new.jpg'\" alt=\"\"\u002F\u003ECarolin Schneider\u003C\u002Fa\u003E\u003Csup\u003E3\u003C\u002Fsup\u003E, \u003Cimg class=\"pr5\" src=\"http:\u002F\u002F3b76aaf63d1816bb57bf-a34624e694c43cdf8b40aa048a644ca4.r96.cf2.rackcdn.com\u002FDesign\u002FImages\u002Fnewprofile_default_profileimage_new.jpg\" alt=\"\"\u002F\u003EVassilios P. Papageorgiou\u003Csup\u003E4\u003C\u002Fsup\u003E, \u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Fpeople\u002Fu\u002F1178735\" class=\"user-id-1178735\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F1178735\u002F24\" onerror=\"this.src='http:\u002F\u002F3b76aaf63d1816bb57bf-a34624e694c43cdf8b40aa048a644ca4.r96.cf2.rackcdn.com\u002FDesign\u002FImages\u002Fnewprofile_default_profileimage_new.jpg'\" alt=\"\"\u002F\u003EAndreana N. Assimopoulou\u003C\u002Fa\u003E\u003Csup\u003E4\u003C\u002Fsup\u003E, \u003Cimg class=\"pr5\" src=\"http:\u002F\u002F3b76aaf63d1816bb57bf-a34624e694c43cdf8b40aa048a644ca4.r96.cf2.rackcdn.com\u002FDesign\u002FImages\u002Fnewprofile_default_profileimage_new.jpg\" alt=\"\"\u002F\u003ENikolaos Tsafantakis\u003Csup\u003E5\u003C\u002Fsup\u003E, \u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Fpeople\u002Fu\u002F132946\" class=\"user-id-132946\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F132946\u002F24\" onerror=\"this.src='http:\u002F\u002F3b76aaf63d1816bb57bf-a34624e694c43cdf8b40aa048a644ca4.r96.cf2.rackcdn.com\u002FDesign\u002FImages\u002Fnewprofile_default_profileimage_new.jpg'\" alt=\"\"\u002F\u003ENikolas Fokialakis\u003C\u002Fa\u003E\u003Csup\u003E5\u003C\u002Fsup\u003E and \u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Fpeople\u002Fu\u002F282149\" class=\"user-id-282149\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F282149\u002F24\" onerror=\"this.src='http:\u002F\u002F3b76aaf63d1816bb57bf-a34624e694c43cdf8b40aa048a644ca4.r96.cf2.rackcdn.com\u002FDesign\u002FImages\u002Fnewprofile_default_profileimage_new.jpg'\" alt=\"\"\u002F\u003EAnne Willems\u003C\u002Fa\u003E\u003Csup\u003E1\u003C\u002Fsup\u003E\u003C\u002Fdiv\u003E\r\n\u003Cul class=\"notes\"\u003E\r\n\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E1\u003C\u002Fsup\u003E\u003C\u002Fspan\u003ELaboratory of Microbiology, Department Biochemistry and Microbiology, Faculty Sciences, Ghent University, Ghent, Belgium\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E2\u003C\u002Fsup\u003E\u003C\u002Fspan\u003ELaboratory of Conservation and Evaluation of Native and Floricultural Species, Institute of Plant Breeding and Genetic Resources, Hellenic Agricultural Organization Demeter, Thessaloniki, Greece\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E3\u003C\u002Fsup\u003E\u003C\u002Fspan\u003EInstitut für Pflanzenkultur, Schnega, Germany\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E4\u003C\u002Fsup\u003E\u003C\u002Fspan\u003EOrganic Chemistry Laboratory, School of Chemical Engineering, Aristotle University of Thessaloniki and Center of Interdisciplinary Research and Innovation of AUTh (CIRI-AUTh), Natural Products Research Centre of Excellence (NatPro-AUTH), Thessaloniki, Greece\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E5\u003C\u002Fsup\u003E\u003C\u002Fspan\u003EDivision of Pharmacognosy and Natural Products Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece\u003C\u002Fli\u003E\r\n\u003C\u002Ful\u003E\r\n\u003Cp class=\"mb0\"\u003EAlkannin and shikonin (A\u002FS) are enantiomeric naphthoquinones produced in the roots of certain plants from the Boraginaceae family such as \u003Ci\u003ELithospermum\u003C\u002Fi\u003E spp. and \u003Ci\u003EAlkanna\u003C\u002Fi\u003E spp. They possess antimicrobial, anti-tumoral and wound healing properties. The production of secondary metabolites by \u003Ci\u003EAlkanna tinctoria\u003C\u002Fi\u003E might be influenced by its endomicrobiome. To study the interaction between this medicinal plant and its bacterial endophytes, we isolated bacteria from the roots of wild growing \u003Ci\u003EAlkanna tinctoria\u003C\u002Fi\u003E collected near to Athens and Thessaloniki in Greece. Representative strains selected by MALDI-TOF mass spectrometry were identified by partial 16S rRNA gene sequence analysis. In total, 197 distinct phylotypes of endophytic bacteria were detected. The most abundant genera recovered were \u003Ci\u003EPseudomonas\u003C\u002Fi\u003E, \u003Ci\u003EXanthomonas\u003C\u002Fi\u003E, \u003Ci\u003EVariovorax\u003C\u002Fi\u003E, \u003Ci\u003EBacillus\u003C\u002Fi\u003E, \u003Ci\u003EInquilinus\u003C\u002Fi\u003E, \u003Ci\u003EPantoea\u003C\u002Fi\u003E, and \u003Ci\u003EStenotrophomonas\u003C\u002Fi\u003E. Several bacteria were then tested \u003Ci\u003Ein vitro\u003C\u002Fi\u003E for their plant growth promoting activity and the production of cell-wall degrading enzymes. Strains of \u003Ci\u003EPseudomonas\u003C\u002Fi\u003E, \u003Ci\u003EPantoea\u003C\u002Fi\u003E, \u003Ci\u003EBacillus\u003C\u002Fi\u003E and \u003Ci\u003EInquilinus\u003C\u002Fi\u003E showed positive plant growth properties whereas those of Bacteroidetes and \u003Ci\u003ERhizobiaceae\u003C\u002Fi\u003E showed pectinase and cellulase activity \u003Ci\u003Ein vitro\u003C\u002Fi\u003E. In addition, bacterial responses to alkannin and shikonin were investigated through resistance assays. Gram negative bacteria were found to be resistant to the antimicrobial properties of A\u002FS, whereas the Gram positives were sensitive. A selection of bacteria was then tested for the ability to induce A\u002FS production in hairy roots culture of \u003Ci\u003EA. tinctoria\u003C\u002Fi\u003E. Four strains belonging to \u003Ci\u003EChitinophaga\u003C\u002Fi\u003E sp., \u003Ci\u003EAllorhizobium\u003C\u002Fi\u003E sp., \u003Ci\u003EDuganella\u003C\u002Fi\u003E sp., and \u003Ci\u003EMicromonospora\u003C\u002Fi\u003E sp., resulted in significantly more A\u002FS in the hairy roots than the uninoculated control. As these bacteria can produce cell-wall degrading enzymes, we hypothesize that the A\u002FS induction may be related with the plant-bacteria interaction during colonization.\u003C\u002Fp\u003E\r\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\r\n\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"JournalFullText\"\u003E\r\n\u003Ca id=\"h2\" name=\"h2\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EIntroduction\u003C\u002Fh2\u003E\r\n\u003Cp class=\"mb15\"\u003EPlants communicate and interact with a wide variety of microorganisms. They release water-soluble sugars, organic acids, ionic compounds, phenolics, hormones, and other metabolites into the rhizosphere, thus providing nutrients to microorganisms. Due to the richness of nutrients in this soil region, compared to bulk soil, the rhizosphere is enriched with microorganisms, leading to increased microbial interactions (\u003Ca href=\"#B71\"\u003ESasse et al., 2018\u003C\u002Fa\u003E; \u003Ca href=\"#B87\"\u003EYu and Hochholdinger, 2018\u003C\u002Fa\u003E). Rhizospheric microorganisms influence plant growth through soil nutrient recycling and nutrient uptake. For example, bacteria such as \u003Ci\u003EAcidobacterium\u003C\u002Fi\u003E sp., \u003Ci\u003EPedobacter\u003C\u002Fi\u003E sp., \u003Ci\u003EMuciliginibacter\u003C\u002Fi\u003E sp., and \u003Ci\u003ECellulomona\u003C\u002Fi\u003Es sp. play an important role in the recycling of plant polysaccharides such as cellulose, pectin and lignin (\u003Ca href=\"#B46\"\u003ELópez-Mondéjar et al., 2016\u003C\u002Fa\u003E; \u003Ca href=\"#B66\"\u003EPoulsen et al., 2016\u003C\u002Fa\u003E; \u003Ca href=\"#B13\"\u003EBelova et al., 2018\u003C\u002Fa\u003E). Several bacteria including those from the genera \u003Ci\u003EPseudomonas\u003C\u002Fi\u003E, \u003Ci\u003EPantoea\u003C\u002Fi\u003E, and \u003Ci\u003EBacillus\u003C\u002Fi\u003E have the ability to solubilize and therefore make accessible insoluble phosphate to plants (\u003Ca href=\"#B26\"\u003EGhyselinck et al., 2013\u003C\u002Fa\u003E). Similarly, rhizobia can provide plants with combined nitrogen via biological nitrogen fixation (\u003Ca href=\"#B48\"\u003EMabrouk et al., 2018\u003C\u002Fa\u003E). Soil microorganisms can also influence plant growth through the secretion of growth hormones such as indole acetic acid (IAA) or ethylene. Indeed, several studies have shown that plant inoculation with IAA-producing bacteria promote plant growth significantly (\u003Ca href=\"#B62\"\u003EPatten and Glick, 2002\u003C\u002Fa\u003E; \u003Ca href=\"#B52\"\u003EMohite, 2013\u003C\u002Fa\u003E; \u003Ca href=\"#B18\"\u003EChandra et al., 2018\u003C\u002Fa\u003E). Furthermore, rhizospheric bacteria can play a role in plant defense and metabolite production (\u003Ca href=\"#B40\"\u003ELambers et al., 2009\u003C\u002Fa\u003E; \u003Ca href=\"#B14\"\u003EBerendsen et al., 2012\u003C\u002Fa\u003E; \u003Ca href=\"#B31\"\u003EHuang et al., 2019\u003C\u002Fa\u003E). They can first compete with pathogens for nutrients and space in the rhizosphere. For instance, siderophore-producing bacteria can contend with soil pathogens for iron uptake and consequently prevent the root colonization by these microorganisms. As iron is essential for the growth of many organisms and is involved in biofilm formation that is needed for successful root colonization, its uptake by beneficial bacteria can prevent pathogen infections (\u003Ca href=\"#B67\"\u003ERamey et al., 2004\u003C\u002Fa\u003E; \u003Ca href=\"#B2\"\u003EAhmed and Holmström, 2014\u003C\u002Fa\u003E). Microorganisms can also produce secondary metabolites with antimicrobial properties. For example, \u003Ci\u003EBurkholderia\u003C\u002Fi\u003E sp. showed antimicrobial activities against the plant pathogens \u003Ci\u003EPhytophthora capsici\u003C\u002Fi\u003E, \u003Ci\u003EFusarium oxysporum\u003C\u002Fi\u003E, and \u003Ci\u003ERhizoctonia solani\u003C\u002Fi\u003E through the production of pyrrolnitrin (\u003Ca href=\"#B33\"\u003EJung et al., 2018\u003C\u002Fa\u003E). In addition, some microbes can induce plant defenses. \u003Ca href=\"#B7\"\u003EAsghari et al. (2020)\u003C\u002Fa\u003E demonstrated that \u003Ci\u003EPseudomonas\u003C\u002Fi\u003E sp. Sn48 and \u003Ci\u003EPantoea\u003C\u002Fi\u003E sp. Sa14 induce plant production of phytoalexins and polyamines resulting in a reduction of the \u003Ci\u003EAgrobacterium tumefaciens\u003C\u002Fi\u003E gall.\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003EAmong the microorganisms interacting with plants, endophytes are defined as those that colonize the internal tissues of plants during the entire or part of their host’s lifecycle without causing external damage (\u003Ca href=\"#B69\"\u003ERyan et al., 2008\u003C\u002Fa\u003E; \u003Ca href=\"#B4\"\u003EAnjum and Chandra, 2015\u003C\u002Fa\u003E; \u003Ca href=\"#B58\"\u003EOrlikowska et al., 2017\u003C\u002Fa\u003E). Like rhizospheric microorganisms, they can promote plant growth and influence plant metabolites. In the case of medicinal plants, endophytes contribute to or are responsible for their host’s pharmaceutical properties (e.g., antioxidant and\u002For antimicrobial properties; \u003Ca href=\"#B36\"\u003EKöberl et al., 2013\u003C\u002Fa\u003E; \u003Ca href=\"#B16\"\u003EBrader et al., 2014\u003C\u002Fa\u003E; \u003Ca href=\"#B49\"\u003EMaggini et al., 2017\u003C\u002Fa\u003E). The inoculation of \u003Ci\u003EBacillus subtilis\u003C\u002Fi\u003E BERA 71 to chickpea increased the plant biomass and reduced the levels of reactive oxygen species and lipid peroxidation under salinity stress. This effect was associated with an enhancement of the activities of enzymatic and non-enzymatic antioxidants (\u003Ca href=\"#B1\"\u003EAbd_Allah et al., 2017\u003C\u002Fa\u003E). Endophytes can also influence the antimicrobial activity as well as the production of secondary metabolites in medicinal plants. \u003Ca href=\"#B59\"\u003EPandey et al. (2018)\u003C\u002Fa\u003E showed that endophytic fungi increase the biomass of \u003Ci\u003EWithania somnifera\u003C\u002Fi\u003E, resulting in a higher total plant withanolide content. Moreover, the inoculation of endophytic bacteria stimulated the withanolide biosynthesis pathway by upregulating the expression of key genes within this pathway such as \u003Ci\u003EHMGR\u003C\u002Fi\u003E, \u003Ci\u003EDXS\u003C\u002Fi\u003E, and \u003Ci\u003EDXR\u003C\u002Fi\u003E (\u003Ca href=\"#B59\"\u003EPandey et al., 2018\u003C\u002Fa\u003E). Endophytes of medicinal plants also produce a wide range of bioactive secondary metabolites such as alkaloids, isoprenoids, flavonoids and indoles (\u003Ca href=\"#B77\"\u003ETan and Zou, 2001\u003C\u002Fa\u003E; \u003Ca href=\"#B11\"\u003EBarman and Bhattacharjee, 2020\u003C\u002Fa\u003E; \u003Ca href=\"#B53\"\u003EMonnanda et al., 2020\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003EStudies on endophytes are indeed invaluable to the promotion of medicinal plants’ therapeutic properties. \u003Ci\u003EAlkanna tinctoria\u003C\u002Fi\u003E (family \u003Ci\u003EBoraginaceae\u003C\u002Fi\u003E) is a medicinal plant native to countries of the Mediterranean region (\u003Ca href=\"#B76\"\u003EStrid, 2016\u003C\u002Fa\u003E). The plant produces quinones and phenolic compounds and has antioxidant activities. Moreover, compared to other \u003Ci\u003EAlkanna\u003C\u002Fi\u003E species, \u003Ci\u003EA. tinctoria\u003C\u002Fi\u003E produces high amounts of alkannin\u002Fshikonin (A\u002FS) and their derivatives. These secondary metabolites are enantiomeric naphthoquinones produced by root tissues. They are sequestered to form granules in the phospholipid layer and are accumulated in the apoplastic spaces. Thus, they can be found in the cork layer of mature roots and their accumulation leads to a red or purple coloration of the root (\u003Ca href=\"#B17\"\u003EBrigham et al., 1999\u003C\u002Fa\u003E; \u003Ca href=\"#B75\"\u003ESingh et al., 2010\u003C\u002Fa\u003E; \u003Ca href=\"#B79\"\u003ETatsumi et al., 2016\u003C\u002Fa\u003E). The A\u002FS derivatives are strongly involved in the antimicrobial activity of the plant and form a chemical barrier against soil-borne microorganisms. They are also known for wound healing, anticancer and anti-inflammatory properties (\u003Ca href=\"#B61\"\u003EPapageorgiou et al., 1999\u003C\u002Fa\u003E, \u003Ca href=\"#B60\"\u003E2008\u003C\u002Fa\u003E) and they comprise the active pharmaceutical ingredients of strong wound healing medicines approved by the National Organization for Medicines in Greece. Because of these interesting traits, \u003Ci\u003EA. tinctoria\u003C\u002Fi\u003E was chosen for the production of A\u002FS for medical applications (\u003Ca href=\"#B60\"\u003EPapageorgiou et al., 2008\u003C\u002Fa\u003E; \u003Ca href=\"#B73\"\u003ESengul et al., 2009\u003C\u002Fa\u003E; \u003Ca href=\"#B82\"\u003ETung et al., 2013\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb0\"\u003EDespite the medicinal importance of wild-growing \u003Ci\u003EA. tinctoria\u003C\u002Fi\u003E and the potential bioactive properties of its associated bacteria, no studies have been performed so far on its endophytic bacteria and their possible interactions with the plant. The aims of this work were therefore (i) to explore the diversity of endophytic bacteria associated with \u003Ci\u003EA. tinctoria\u003C\u002Fi\u003E, (ii) to screen the isolates for a number of plant-growth promotion properties and for the production of cell-wall degrading enzymes (iii) to evaluate the effect of the A\u002FS produced by the plant on the associated bacteria, and (iv) to test their effect on plant A\u002FS production in a bioassay.\u003C\u002Fp\u003E\r\n\u003Ca id=\"h3\" name=\"h3\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EMaterials and Methods\u003C\u002Fh2\u003E\r\n\u003Ch3 class=\"pt0\"\u003EIsolation of Root Endophytic Bacteria From Wild-Growing \u003Ci\u003EAlkanna tinctoria\u003C\u002Fi\u003E Plants\u003C\u002Fh3\u003E\r\n\u003Cp class=\"mb15\"\u003EThree botanical expeditions to collect wild-growing \u003Ci\u003EAlkanna tinctoria\u003C\u002Fi\u003E were undertaken. The first one was conducted in December 2017, in Northern Greece (Seich Sou area close to the Theater of the Earth, Thessaloniki, Greece), using a special collection permit obtained by the Institute of Plant Breeding and Genetic Resources, Hellenic Agricultural Organization Demeter (IPBGR, HAO Demeter) which is issued annually by the Greek Ministry of Environment and Energy. Samples from this expedition were used to optimize the isolation conditions. The wild plants collected were taxonomically identified and they were given the International Plant Exchange Network (IPEN) accession number GR-1-BBGK-18,6081 for their long-term \u003Ci\u003Eex situ\u003C\u002Fi\u003E conservation (including also asexual and \u003Ci\u003Ein vitro\u003C\u002Fi\u003E propagation trials) at the premises of IPBGR, HAO Demeter. Two further collections were made in April and May of 2018 in Southern Greece (at the University of Athens, Campus of Zografou, Athens) and Northern Greece (Seich Sou area, Thessaloniki), respectively.\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003EAfter each expedition, a bacterial isolation campaign was conducted. Three plants from each of the collections were chosen to explore the diversity of culturable bacterial endophytes. The roots were first cleaned with tap water to remove soil particles. Subsequently, they were immersed in a solution of 70% ethanol for 5 min. After rinsing with sterile water, the root was further sterilized with a solution of 1.4% of NaOCl for 20 min. The root was rinsed again and immersed in 2% Na\u003Csub\u003E2\u003C\u002Fsub\u003ES\u003Csub\u003E2\u003C\u002Fsub\u003EO\u003Csub\u003E3\u003C\u002Fsub\u003E for 10 min to neutralize the effect of bleach. A last rinse with sterile water was performed before testing the efficiency of the sterilization process in order to exclude non-endophytes. To do so, the external surface of the root was imprinted onto a sterile plate containing 869 agar medium (\u003Ca href=\"#B83\"\u003EWeyens et al., 2012\u003C\u002Fa\u003E; \u003Ca href=\"#B22\"\u003EEevers et al., 2015\u003C\u002Fa\u003E) before incubation at 28°C. Only roots without microbial growth on the imprints were used for the isolation of endophytic bacteria. The root material was crushed in 10 mL of sterile phosphate buffer saline (PBS) and a 10-fold dilution series was prepared. The dilutions 10\u003Csup\u003E–2\u003C\u002Fsup\u003E–10\u003Csup\u003E–7\u003C\u002Fsup\u003E were then plated in triplicate.\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb0\"\u003ETo determine the isolation conditions (medium, incubation time and temperature) that would yield the widest bacterial diversity, during the first isolation campaign a wide selection of media were compared. Nine culture media supplemented with 50 mg\u002FL cycloheximide were tested, including the commonly used media R2A (Difco), 1\u002F10 TSA (Oxoid), and ISP2 (Oxoid), as well as 1\u002F10 869 medium (\u003Ca href=\"#B22\"\u003EEevers et al., 2015\u003C\u002Fa\u003E) which is routinely used for the isolation of endophytes. In addition, 1\u002F10 869 medium supplemented with either an infusion of dried \u003Ci\u003ESymphytum officinale\u003C\u002Fi\u003E (family \u003Ci\u003EBoraginaceae\u003C\u002Fi\u003E) roots or with allantoin was tested. To prepare the former medium supplement, dried \u003Ci\u003ES. officinale\u003C\u002Fi\u003E roots (Bioshop, Gent, Belgium) were infused in boiled water for 10 min (28 g\u002FL). The infusion was then filtered and used to resuspend the dry ingredients of medium 1\u002F10 869. Allantoin was added to medium 1\u002F10 869 at four concentrations (0.32, 1.6, 9, 32 mM). Allantoin is a secondary metabolite found in the root of several members of the \u003Ci\u003EBoraginaceae\u003C\u002Fi\u003E family (\u003Ca href=\"#B22\"\u003EEevers et al., 2015\u003C\u002Fa\u003E; \u003Ca href=\"#B20\"\u003EDresler et al., 2017\u003C\u002Fa\u003E). In this first isolation campaign, plates were incubated at 28°C for 4 days after which all distinct colony types were picked for purification. Plates of the highest dilutions were incubated for an additional 10 days at 20°C to isolate slow growers.\u003C\u002Fp\u003E\r\n\u003Ch3\u003EIdentification of the Isolates\u003C\u002Fh3\u003E\r\n\u003Cp class=\"mb15\"\u003EDereplication and identification of the isolates obtained in the different conditions were performed using MALDI-TOF MS and 16S rRNA gene sequencing. To conduct the MALDI-TOF MS, pure 2nd generation cultures were grown. The proteins were then extracted, spotted in duplicate onto MALDI-TOF target plates and overlaid with matrix solution (10 mg\u002FmL α-cyano-4-hydroxycinnamic acid in acetonitrile-water-trifluoroacetic acid) as previously described (\u003Ca href=\"#B21\"\u003EDumolin et al., 2019\u003C\u002Fa\u003E). The protein profiles were read with the Bruker Microflex\u003Csup\u003ETM\u003C\u002Fsup\u003E LT\u002FSH system. The programs SPeDE (\u003Ca href=\"#B21\"\u003EDumolin et al., 2019\u003C\u002Fa\u003E) and BioNumerics (Applied Mats) were used to cluster the protein profiles. In SPeDe, each unique spectrum is assigned as a reference and clusters of all similar spectra are generated (\u003Ca href=\"#B21\"\u003EDumolin et al., 2019\u003C\u002Fa\u003E). Thus, strains from which the spectra clustered together were considered as highly similar and only the reference strains were selected for rRNA 16S gene sequencing (\u003Ca href=\"#B32\"\u003EJain et al., 2018\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb0\"\u003EGenomic DNA was extracted by alkaline lysis according to the method of \u003Ca href=\"#B56\"\u003ENiemann et al. (1997)\u003C\u002Fa\u003E. Amplification of the 16S rRNA gene was performed using primers pA (3′-AGAGTTTGATCCTGGCTCAG-5′, forward) and pH (5′-AAGGAGGTGATCCAGCCGCA-3′, reverse). The PCR products were sequenced by Eurofins Genomics, Mix2seq service, with the BKL1 primer (5′-GTATTACCGCGGCTGCTGGCA-3′, reverse) and the sequences obtained were identified with EzTaxon database (\u003Ca href=\"#B86\"\u003EYoon et al., 2017\u003C\u002Fa\u003E). We considered two sequences as belonging to the same species when they were at least 98.7% identical and as belonging to the same genus when they were at least 94.8% identical (\u003Ca href=\"#B54\"\u003EMoreira and López-García, 2014\u003C\u002Fa\u003E; \u003Ca href=\"#B84\"\u003EYarza et al., 2014\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Ch3\u003EPlant Growth-Promoting Activity of Endophytic Bacteria\u003C\u002Fh3\u003E\r\n\u003Cp class=\"mb0\"\u003ETo test bacteria \u003Ci\u003Ein vitro\u003C\u002Fi\u003E for their plant growth promoting activity, four parameters were evaluated: phosphate solubilization, siderophore production, ACC deaminase activity, and indole acetic acid production.\u003C\u002Fp\u003E\r\n\u003Ch4\u003EPhosphate Solubilization\u003C\u002Fh4\u003E\r\n\u003Cp class=\"mb0\"\u003ENBRIP medium (2.5 g\u002FL Ca\u003Csub\u003E3\u003C\u002Fsub\u003E(PO\u003Csub\u003E4\u003C\u002Fsub\u003E); 5 g\u002FL MgCl\u003Csub\u003E2\u003C\u002Fsub\u003E,6H\u003Csub\u003E2\u003C\u002Fsub\u003EO; 0.25 g\u002FL MgSO\u003Csub\u003E4\u003C\u002Fsub\u003E,7H\u003Csub\u003E2\u003C\u002Fsub\u003EO; 0.2 g\u002FL KCl, 0.1 g\u002FL (NH\u003Csub\u003E4\u003C\u002Fsub\u003E)\u003Csub\u003E2\u003C\u002Fsub\u003ESO\u003Csub\u003E4\u003C\u002Fsub\u003E, and 15 g\u002FL agar) with 10 g\u002FL glucose was used for this test (\u003Ca href=\"#B55\"\u003ENautiyal, 1999\u003C\u002Fa\u003E). The pH of the medium was adjusted to 7 before autoclaving and small Petri dishes were used (diameter 5.5 cm). Dense bacterial suspensions (OD 0.5–0.6) were made in 1 mL of PBS. Then, 10 μL of each suspension was spotted in the middle of each plate. The test was performed in triplicate. The diameter of clear halos around the bacterial growth was measured after 2, 4, 7, and 10 days of incubation at 28°C. The strain R-42086 (\u003Ci\u003EPseudomonas\u003C\u002Fi\u003E sp.) was used as a positive control (\u003Ca href=\"#B26\"\u003EGhyselinck et al., 2013\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Ch4\u003ESiderophore Production\u003C\u002Fh4\u003E\r\n\u003Cp class=\"mb0\"\u003ETo test the production of siderophores, the CAS (chrome azurol S) blue medium was prepared according to \u003Ca href=\"#B47\"\u003ELouden et al. (2011)\u003C\u002Fa\u003E. Small Petri dishes were used (diameter 5.5 cm). Dense bacterial suspensions (OD 0.5–0.6) were made in 1 mL of sterile PBS. Then, 10 μL of each suspension was spotted in the middle of each plate. The test was performed in triplicate. The halo diameter was observed and measured after 2, 4, 7, and 10 days of incubation at 28°C. The strain R-42086 (\u003Ci\u003EPseudomonas\u003C\u002Fi\u003E sp.) was used as a positive control (\u003Ca href=\"#B26\"\u003EGhyselinck et al., 2013\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Ch4\u003E1-Aminocyclopropane-1-Carboxylate (ACC) Deaminase Activity\u003C\u002Fh4\u003E\r\n\u003Cp class=\"mb0\"\u003EDFS medium was prepared for the ACC deaminase test following the protocol from \u003Ca href=\"#B63\"\u003EPenrose and Glick (2003)\u003C\u002Fa\u003E. The glucose and the citric acid were filter sterilized and added to the autoclaved medium. To conduct the experiment, the bacteria were first grown in DFS medium + 2 g (NH\u003Csub\u003E4\u003C\u002Fsub\u003E)\u003Csub\u003E2\u003C\u002Fsub\u003ESO\u003Csub\u003E4\u003C\u002Fsub\u003E for 72 h at 28°C, 100 rpm. Then, in a 96-well plate, for each strain 15 μL of the liquid culture was added in 135 μL of DFS medium + 3 mM ACC. Each strain was tested in triplicate. The DFS medium without any nitrogen source was used as control. As blanks, the outermost wells of the plate were filled with the culture medium free of bacteria. After 48 h at 28°C, the OD was read at 590 nm. Then, 50 μL of the culture was re-transferred to fresh DFS + 0.3 M ACC. This procedure was repeated twice to exhaust any residual stock of nitrogen. The strain R-42058 \u003Ci\u003E(Pseudomonas\u003C\u002Fi\u003E sp.) was used as a positive control and the ACC deaminase activity was evaluated by comparison with the blank (\u003Ca href=\"#B26\"\u003EGhyselinck et al., 2013\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Ch4\u003EIAA Production\u003C\u002Fh4\u003E\r\n\u003Cp class=\"mb15\"\u003EYeast malt extract medium (YM, peptone 5 g\u002FL, yeast extract 3 g\u002FL, malt extract 3 g\u002FL, pH 6.2) was used to test for the production of indole acetic acid (IAA) in liquid culture (\u003Ca href=\"#B5\"\u003EApine and Jadhav, 2011\u003C\u002Fa\u003E; \u003Ca href=\"#B52\"\u003EMohite, 2013\u003C\u002Fa\u003E). Bacteria were grown in R2B medium (Difco) for 72 h at 28°C, 100 rpm. Then, 1.5 mL of each bacterial culture was centrifuged (20°C, 5 min, 14,000 rpm), the supernatant was removed, and the pellet was resuspended in sterile distilled water. Then, 100 μL of the suspension were inoculated in 900 μL of YM medium with and without tryptophan (1 g\u002FL). The outermost wells of the plate were filled with the culture medium free of bacteria as blanks. The test was performed in triplicate. Incubation was at 28°C for 72 h. The strain R-42086 (\u003Ci\u003EPseudomonas\u003C\u002Fi\u003E sp.) was used as a positive control (\u003Ca href=\"#B26\"\u003EGhyselinck et al., 2013\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb0\"\u003EAfter incubation, the plates were centrifuged at 20°C, 3,700 rpm for 5 min. Then, 50 μL of the supernatant was transferred to flat bottom 96-wells plate and 100 μL of Salkowsky’s reagent (2% 0.5 M FeCl\u003Csub\u003E3\u003C\u002Fsub\u003E in 35% HClO\u003Csub\u003E4\u003C\u002Fsub\u003E solution) was added and mixed by pipetting. The plate was then kept in the dark for 30 min before measuring the optical density. A calibration curve was made with 0, 0.5, 1, 2, 5, 10, 15, 20, 25, 30 μg of IAA\u002FmL.\u003C\u002Fp\u003E\r\n\u003Ch3\u003EEnzymatic Activities\u003C\u002Fh3\u003E\r\n\u003Cp class=\"mb0\"\u003EOur isolates’ ability to recycle plant polysaccharides such as cellulose, pectin and lignin was tested through phenotypic enzymatic assays.\u003C\u002Fp\u003E\r\n\u003Ch4\u003EPectinase and Cellulase Activities\u003C\u002Fh4\u003E\r\n\u003Cp class=\"mb0\"\u003EDepending on the objective of the test, a minimum medium (4 g\u002FL KH\u003Csub\u003E2\u003C\u002Fsub\u003EPO\u003Csub\u003E4\u003C\u002Fsub\u003E, 6 g\u002FL Na\u003Csub\u003E2\u003C\u002Fsub\u003EHPO\u003Csub\u003E4\u003C\u002Fsub\u003E, 2 g\u002FL (NH\u003Csub\u003E4\u003C\u002Fsub\u003E)\u003Csub\u003E2\u003C\u002Fsub\u003ESO\u003Csub\u003E4\u003C\u002Fsub\u003E, 1 g\u002FL yeast extract, 0.001 g\u002FL FeSO\u003Csub\u003E4\u003C\u002Fsub\u003E, 0.2 g\u002FL MgSO\u003Csub\u003E4\u003C\u002Fsub\u003E, 0.001 g\u002FL CaCl\u003Csub\u003E2\u003C\u002Fsub\u003E, 0.00001 g\u002FL H\u003Csub\u003E3\u003C\u002Fsub\u003EBO\u003Csub\u003E3\u003C\u002Fsub\u003E, 0.00001 g\u002FL MnSO\u003Csub\u003E4\u003C\u002Fsub\u003E, 0.00007 g\u002FL ZnSO\u003Csub\u003E4\u003C\u002Fsub\u003E, 0.00005 g\u002FL CuSO\u003Csub\u003E4\u003C\u002Fsub\u003E, 0.00001 g\u002FL MoO\u003Csub\u003E3\u003C\u002Fsub\u003E, 15 g\u002FL agar, pH 7) supplemented with 5 g\u002FL of either pectin or carboxymethyl cellulose was used for this assay. Dense bacterial suspensions were made in sterile PBS (OD 0.5–0.6). Then, 10 μL of each bacterial suspension was spotted onto the center of the plate. The test was performed in triplicates and plates were incubated at 28°C for 5 days. Plates were then checked for the presence of a solubilization halo. The halo was visualized by the addition of 0.01% congo red and 1% hexadecyltrimethylammonium bromide (CTAB) solutions for the cellulase and pectinase tests, respectively. The strain LMG 16323 (\u003Ci\u003ECellulomonas cellasea\u003C\u002Fi\u003E) was used as a positive control for the cellulase assay whilst strain LMG 2404 (\u003Ci\u003EPectobacterium carotovorum\u003C\u002Fi\u003E subsp. \u003Ci\u003Ecarotovorum\u003C\u002Fi\u003E) was used as a positive control for the pectinase test.\u003C\u002Fp\u003E\r\n\u003Ch4\u003ELigninolytic Activity\u003C\u002Fh4\u003E\r\n\u003Cp class=\"mb15\"\u003EThis assay was conducted in two steps: a first screening on minimum medium (4 g\u002FL KH\u003Csub\u003E2\u003C\u002Fsub\u003EPO\u003Csub\u003E4\u003C\u002Fsub\u003E, 6 g\u002FL Na\u003Csub\u003E2\u003C\u002Fsub\u003EHPO\u003Csub\u003E4\u003C\u002Fsub\u003E, 2 g\u002FL (NH\u003Csub\u003E4\u003C\u002Fsub\u003E)\u003Csub\u003E2\u003C\u002Fsub\u003ESO\u003Csub\u003E4\u003C\u002Fsub\u003E, 1 g\u002FL yeast extract, 0.001 g\u002FL FeSO\u003Csub\u003E4\u003C\u002Fsub\u003E, 0.2 g\u002FL MgSO\u003Csub\u003E4\u003C\u002Fsub\u003E, 0.001 g\u002FL CaCl\u003Csub\u003E2\u003C\u002Fsub\u003E, 0.00001 g\u002FL H\u003Csub\u003E3\u003C\u002Fsub\u003EBO\u003Csub\u003E3\u003C\u002Fsub\u003E, 0.00001 g\u002FL MnSO\u003Csub\u003E4\u003C\u002Fsub\u003E, 0.00007 g\u002FL ZnSO\u003Csub\u003E4\u003C\u002Fsub\u003E, 0.0000 5 g\u002FL CuSO\u003Csub\u003E4\u003C\u002Fsub\u003E, 0.00001 g\u002FL MoO\u003Csub\u003E3\u003C\u002Fsub\u003E, 15 g\u002FL agar, pH 7) supplemented with 5 g\u002FL lignin and a second test of selected bacteria on the same minimum medium with 25 mg\u002FL of methylene blue.\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003ETo screen for ligninolytic activity, dense bacterial suspensions (OD 0.5–0.6) were made in sterile PBS. Then, 10 μL of each bacterial suspension was spotted onto the middle of the plate. The experiment was conducted in triplicates and the plates were incubated at 28°C for 5 days before checking for bacterial growth. Bacteria that were able to grow on lignin medium were transferred two more times to the same medium to ensure that survival was independent of the previous nutrient stock.\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb0\"\u003EAfter a total of three transfers, strains that retained the ability to grow were selected to check for their ability to solubilize methylene blue. Structurally, methylene blue is very similar to lignin and both compounds can be degraded by the same enzymes. When methylene blue is degraded, it loses its color and can therefore be used to identify lignin-degrading bacteria (\u003Ca href=\"#B10\"\u003EBandounas et al., 2011\u003C\u002Fa\u003E). Dense bacterial suspensions were made in sterile PBS. Then, 10 μL of each bacterial suspension was spotted onto the middle of the plate. The plates were incubated for 1 week at 28°C and growth was checked daily. Bacteria able to metabolize methylene blue are expected to produce bright halos around their colonies.\u003C\u002Fp\u003E\r\n\u003Ch3\u003ESusceptibility Assay\u003C\u002Fh3\u003E\r\n\u003Cp class=\"mb0\"\u003ESusceptibility assays were conducted to assess the sensitivity of \u003Ci\u003EA. tinctoria\u003C\u002Fi\u003E endophytic bacteria isolates to the antimicrobial effects of A\u002FS derivatives. The diffusion assay using filter disks described by \u003Ca href=\"#B12\"\u003EBauer et al. (1966)\u003C\u002Fa\u003E was performed. The concentration tested was 50 μg per filter disk, following \u003Ca href=\"#B17\"\u003EBrigham et al. (1999)\u003C\u002Fa\u003E. A mixture of alkannin\u002Fshikonin and their derivatives (A\u002FS mixture) was isolated after extraction and further fractionation steps from \u003Ci\u003EA. tinctoria\u003C\u002Fi\u003E roots, as described in \u003Ca href=\"#B8\"\u003EAssimopoulou et al. (2008)\u003C\u002Fa\u003E and \u003Ca href=\"#B78\"\u003ETappeiner et al. (2013)\u003C\u002Fa\u003E. The mixture was first solubilized in acetone to a concentration of 46.7 mg\u002FmL and then diluted in sterile water to a concentration of 2.5 mg\u002FmL. Then, 20 μL of each test solution were used to inoculate the filter disks. In total, six filter disks were used in this assay: three were inoculated with the A\u002FS mixture (50 μg\u002Ffilter disk), one with acetone-water solution (5.9% acetone; used as an A\u002FS mixture solvent control), one with ampicillin (50 μg\u002Ffilter disk; as a control antibiotic), and one with MilliQ water (as ampicillin solvent control). Dense bacterial suspensions were prepared in PBS and 100 μL of each suspension was inoculated by spreading on R2A plates. Individual filter disks containing 20 μL of each test solution were left to dry for 30 min before being transferred onto the plates. The test was performed in triplicate. Control strains were selected based on the results reported by \u003Ca href=\"#B17\"\u003EBrigham et al. (1999)\u003C\u002Fa\u003E: LMG 8224 \u003Ci\u003E(Staphylococcus aureus\u003C\u002Fi\u003E subsp. \u003Ci\u003Eaureus\u003C\u002Fi\u003E) and LMG 7135 (\u003Ci\u003EBacillus subtilis\u003C\u002Fi\u003E subsp. \u003Ci\u003Esubtilis\u003C\u002Fi\u003E) as sensitive strains and LMG 8223 (\u003Ci\u003EEscherichia coli\u003C\u002Fi\u003E) as a resistant strain.\u003C\u002Fp\u003E\r\n\u003Ch3\u003EInduction of A\u002FS Production in Hairy Roots of \u003Ci\u003EA. tinctoria\u003C\u002Fi\u003E\u003C\u002Fh3\u003E\r\n\u003Cp class=\"mb15\"\u003EHairy roots of \u003Ci\u003EA. tinctoria\u003C\u002Fi\u003E were produced with a modified protocol (\u003Ca href=\"#B17\"\u003EBrigham et al., 1999\u003C\u002Fa\u003E; \u003Ca href=\"#B24\"\u003EFukui et al., 1999\u003C\u002Fa\u003E; \u003Ca href=\"#B35\"\u003EKim et al., 2009\u003C\u002Fa\u003E) as follows: \u003Ci\u003EAgrobacterium rhizogenes\u003C\u002Fi\u003E strain LMG 149 was grown in 40 mL Nutrient Broth (Difco) medium at 28°C for 48 h in the dark and at 100 rpm agitation. The leaves of sterile \u003Ci\u003EA. tinctoria\u003C\u002Fi\u003E explants provided by IPBGR, HAO Demeter (Thessaloniki, Greece) were cut and inoculated at different spots with a syringe filled with a bacterial solution of \u003Ci\u003EA. rhizogenes\u003C\u002Fi\u003E (OD = 0.5–0.6). Each inoculated leaf was transferred onto solid Murashige and Skoog (MS, Duchefa) medium supplemented with 3% sucrose and 0.8% phytoagar (Duchefa) and kept for 1 week at 25°C in the dark until roots appeared. As a control, non-inoculated leaves were cultivated under the same conditions. Developing roots (approximately 1 cm in length), were cut off and transferred weekly (for a period of 3–4 weeks) to a new MS solid medium containing 1% sucrose, 0.8% phytoagar, and 500 mg\u002FL of cefotaxime. The roots were then propagated in liquid MS medium supplemented with 3% sucrose (\u003Ca href=\"#B17\"\u003EBrigham et al., 1999\u003C\u002Fa\u003E; \u003Ca href=\"#B24\"\u003EFukui et al., 1999\u003C\u002Fa\u003E; \u003Ca href=\"#B35\"\u003EKim et al., 2009\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003ETo evaluate the ability of bacteria to induce A\u002FS production in the hairy roots of \u003Ci\u003EA. tinctoria\u003C\u002Fi\u003E, a first screening was performed in 6-well plates. The bacteria for this test were selected based either on their plant growth promoting properties or their enzymatic activities. Firstly, 7 mL of MS + 1% sucrose medium were added to each well, followed by the aseptic addition of young root segments. Bacteria were inoculated to a final OD of 0.001\u002FmL. One 6-well plate was prepared per strain. In addition, an uninoculated control plate was prepared. Plates were incubated in the dark at 100 rpm agitation at 25°C for 1 week. The roots from individual wells were pooled per plate and lyophilized. The extraction of A\u002FS was conducted overnight with 8 mg of dried roots in 250 μL of methanol and the OD was read at 520 nm (\u003Ca href=\"#B9\"\u003EAssimopoulou et al., 2009\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb0\"\u003EAmong seven candidates showing an OD > 0.2 at 520 nm in the first screening, four were subsequently tested in a larger volume. Five 100 mL Erlenmeyer filled with 50 mL of MS + 1% sucrose medium were used per treatment. Pieces of young roots were then carefully added in each Erlenmeyer and incubated for 1 week at 25°C (100 rpm). The Erlenmeyers were then randomized before being inoculated with bacteria to a final OD of 0.001. One uninoculated control (5 replicates) was also prepared. Erlenmeyers were incubated for 1 week at 25°C (100 rpm). The roots from each Erlenmeyer were collected and lyophilized. The extraction was conducted overnight using 40 mg of dried roots in 1,250 μL of methanol. The OD was read at 520 nm and one-factor Anova followed by a Neuman-Keuls test was conducted on the results with the software R x64 3.1.0.\u003C\u002Fp\u003E\r\n\u003Ca id=\"h4\" name=\"h4\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EResults\u003C\u002Fh2\u003E\r\n\u003Ch3 class=\"pt0\"\u003EIsolation and Identification of Root Endophytic Bacteria\u003C\u002Fh3\u003E\r\n\u003Cp class=\"mb0\"\u003EFor our study nine different populations of endogenous \u003Ci\u003EAlkanna tinctoria\u003C\u002Fi\u003E from Northern and Southern Greece have been explored. The first isolation campaign assessed the media that would allow the growth of a wide diversity of culturable bacteria and yielded 1,483 isolates. MALDI-TOF mass spectra of these isolates were compared and grouped, resulting in 914 representative strains that were selected for genotypic identification by 16S rRNA gene sequencing. This allowed identification of 142 distinct phylotypes of endophytic bacteria following the classification threshold values at genus or species level introduced by \u003Ca href=\"#B54\"\u003EMoreira and López-García (2014)\u003C\u002Fa\u003E and \u003Ca href=\"#B84\"\u003EYarza et al. (2014)\u003C\u002Fa\u003E. The number of isolates and phylotypes recovered for each plant sample and medium is available in \u003Ca href=\"#S9\"\u003ESupplementary Table S1\u003C\u002Fa\u003E. The coverage of bacterial diversity for each medium tested was obtained by dividing the number of unique phylotypes from the selected medium by the total number of phylotypes. The media that yielded the highest diversity were medium 1\u002F10 869 supplemented with 32 mM allantoin and medium 1\u002F10 TSA (\u003Ca href=\"#T1\"\u003ETable 1\u003C\u002Fa\u003E). Moreover, media R2A, 1\u002F10 869 and 1\u002F10 869 supplemented with 0.32 mM allantoin allowed the cultivation of members of additional genera including \u003Ci\u003EAcidovorax\u003C\u002Fi\u003E, \u003Ci\u003EMicromonospora\u003C\u002Fi\u003E, \u003Ci\u003EKocuria\u003C\u002Fi\u003E, \u003Ci\u003EDiaminobutyricimonas\u003C\u002Fi\u003E, and \u003Ci\u003EMuciliginibacter\u003C\u002Fi\u003E (\u003Ca href=\"#S9\"\u003ESupplementary Figure S1\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"Imageheaders\"\u003ETABLE 1\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"FigureDesc\"\u003E\r\n\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F633488\u002Ffmicb-12-633488-HTML\u002Fimage_m\u002Ffmicb-12-633488-t001.jpg\" name=\"table1\" target=\"_blank\"\u003E\r\n\u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F633488\u002Ffmicb-12-633488-HTML\u002Fimage_t\u002Ffmicb-12-633488-t001.gif\" id=\"T1\" alt=\"www.frontiersin.org\" \u002F\u003E\u003C\u002Fa\u003E\r\n\u003Cp\u003E\u003Cstrong\u003ETable 1.\u003C\u002Fstrong\u003E Coverage of bacterial diversity of different media, where the number of unique phylotypes in the selected medium wasdivided by the total number of detected phylotypes is given inpercentage (%).\u003C\u002Fp\u003E\r\n\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cp class=\"mb15 w100pc float_left mt15\"\u003EFor the isolation from the second and third collection campaigns, the media R2A, 1\u002F10 TSA, 1\u002F10 869 and 1\u002F10 869 + 32 mM allantoin were used to maximize the culturable diversity. Moreover, the first isolation campaign indicated that extended incubation at 20°C led to a 15.2% increase in diversity at higher dilutions. Most of these isolates were slow-growing Gram-positive bacteria including \u003Ci\u003EMycobacterium\u003C\u002Fi\u003E sp., \u003Ci\u003EMicromonospora\u003C\u002Fi\u003E sp., \u003Ci\u003ELysinimonas\u003C\u002Fi\u003E sp., and \u003Ci\u003EMicrococcus\u003C\u002Fi\u003E sp. Then in further isolations, the plates were incubated at 20°C for 2 weeks and colonies were picked after 1 and 2 week(s), respectively.\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb0\"\u003EThe second and third isolation campaigns using four media only yielded 770 and 582 isolates, respectively. Together with the isolates from the first campaign, this gave 2835 primary bacterial isolates in total. Protein profiles of all these isolates were compared by MALDI-TOF MS and grouped. This allowed the selection of 1,428 representative strains, 914 of which had already been identified by 16S rRNA gene sequencing in the first isolation campaign. The remaining 514 representative strains were also identified by 16S rRNA gene sequencing. In total, among the 1,428 selected representative strains, 197 unique phylotypes were recovered, belonging to 14 genera of Actinobacteria, 6 genera of Bacteroidetes, 11 genera of Firmicutes, and 44 genera of Proteobacteria. Also, three potentially new genera and 40 potentially new species were recovered from the roots of wild \u003Ci\u003EA. tinctoria\u003C\u002Fi\u003E plants. The bacteria were distributed in four phyla, i.e., Bacteroidetes, Proteobacteria, Actinobacteria, and Firmicutes. The plants of the third isolation campaign yielded relatively more Gram positive bacteria (Actinobacteria and Firmicutes) compared to the other plants. Similarly, the plants of the 1st and 2nd isolation campaigns yielded more Alphaproteobacteria and Gammaproteobacteria, respectively (\u003Ca href=\"#S9\"\u003ESupplementary Figure S2\u003C\u002Fa\u003E). Most of the isolates belonged to the Proteobacteria, particularly the Gammaproteobacteria, Alphaproteobacteria, and Betaproteobacteria. Members of the genera \u003Ci\u003EPseudomonas\u003C\u002Fi\u003E were found in eight of the nine plants studied, whereas \u003Ci\u003EPantoea, Xanthomonas\u003C\u002Fi\u003E and \u003Ci\u003EBacillus\u003C\u002Fi\u003E were recovered from seven \u003Ci\u003EA. tinctoria\u003C\u002Fi\u003E plants. Additionally, representatives of \u003Ci\u003EStenotrophomonas\u003C\u002Fi\u003E were found in six of the nine plants (\u003Ca href=\"#F1\"\u003EFigure 1\u003C\u002Fa\u003E). These genera were also isolated from all the tested media (1\u002F10 869, 1\u002F10 869 + 32 mM allantoin, 1\u002F10 TSA and R2A). The isolates that were less than 94.8% similar to the type strain of any bacterial species represent four potentially new genera which are related to \u003Ci\u003EFilimonas\u003C\u002Fi\u003E, \u003Ci\u003EBordetella\u003C\u002Fi\u003E, \u003Ci\u003ECohnella\u003C\u002Fi\u003E and \u003Ci\u003EPaenibacillus\u003C\u002Fi\u003E. Moreover, 40 bacterial strains that were less than 98.7% similar to the type strain of any bacterial species probably represent potential new species. Of these, members of the Bacteroidetes are related to \u003Ci\u003EChitinophaga\u003C\u002Fi\u003E, \u003Ci\u003EFlavobacterium\u003C\u002Fi\u003E, \u003Ci\u003EMucilaginibacter\u003C\u002Fi\u003E, and \u003Ci\u003EPedobacter\u003C\u002Fi\u003E. Potentially new species within the Phylum Firmicutes are related to \u003Ci\u003EBacillus\u003C\u002Fi\u003E, \u003Ci\u003ECohnella\u003C\u002Fi\u003E, \u003Ci\u003EDomibacillus\u003C\u002Fi\u003E, \u003Ci\u003EPaenibacillus\u003C\u002Fi\u003E, and \u003Ci\u003ETumebacillus\u003C\u002Fi\u003E. Potentially new Proteobacteria isolates are related to \u003Ci\u003EAcinetobacter\u003C\u002Fi\u003E, \u003Ci\u003EAllorhizobium\u003C\u002Fi\u003E, \u003Ci\u003EBeijerinckia\u003C\u002Fi\u003E, \u003Ci\u003EBradyrhizobium\u003C\u002Fi\u003E, \u003Ci\u003EBrevundimonas\u003C\u002Fi\u003E, \u003Ci\u003EJanthinobacterium\u003C\u002Fi\u003E, \u003Ci\u003EMassilia\u003C\u002Fi\u003E, \u003Ci\u003EOchrobactrum\u003C\u002Fi\u003E, \u003Ci\u003EPseudomonas\u003C\u002Fi\u003E, \u003Ci\u003ERoseomonas\u003C\u002Fi\u003E, \u003Ci\u003ERhizobium\u003C\u002Fi\u003E, \u003Ci\u003ERhizorhapis\u003C\u002Fi\u003E, \u003Ci\u003EShinella\u003C\u002Fi\u003E, \u003Ci\u003ESphingobium\u003C\u002Fi\u003E, \u003Ci\u003ESphingomonas\u003C\u002Fi\u003E, and \u003Ci\u003EStenotrophomonas\u003C\u002Fi\u003E. Finally, potentially new isolated Actinobacteria members are related to the genera \u003Ci\u003ECellulomas\u003C\u002Fi\u003E, \u003Ci\u003EConexibacter\u003C\u002Fi\u003E, \u003Ci\u003EDiaminobutyricimonas\u003C\u002Fi\u003E, \u003Ci\u003ELysinimonas\u003C\u002Fi\u003E, \u003Ci\u003EMycobacterium\u003C\u002Fi\u003E, and \u003Ci\u003ENocardioide\u003C\u002Fi\u003Es.\u003C\u002Fp\u003E\r\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 1\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"FigureDesc\"\u003E\r\n\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F633488\u002Ffmicb-12-633488-HTML\u002Fimage_m\u002Ffmicb-12-633488-g001.jpg\" name=\"figure1\" target=\"_blank\"\u003E\r\n\u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F633488\u002Ffmicb-12-633488-HTML\u002Fimage_t\u002Ffmicb-12-633488-g001.gif\" id=\"F1\" alt=\"www.frontiersin.org\" \u002F\u003E\u003C\u002Fa\u003E\r\n\u003Cp\u003E\u003Cstrong\u003EFigure 1.\u003C\u002Fstrong\u003E Diversity of genera isolated from wild-growing \u003Ci\u003EAlkanna tinctoria\u003C\u002Fi\u003E plants and the number of plant individuals in which they were found. The number of species found per genus is specified in parentheses. Different colors correspond to specific bacterial phyla or classes.\u003C\u002Fp\u003E\r\n\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Ch3\u003EPlant Growth-Promoting Activity\u003C\u002Fh3\u003E\r\n\u003Cp class=\"mb0\"\u003EOne hundred and twenty-seven strains which represented most of the bacterial diversity recovered, were tested for their plant growth promoting activity \u003Ci\u003Ein vitro\u003C\u002Fi\u003E. The results are summarized in \u003Ca href=\"#F2\"\u003EFigure 2\u003C\u002Fa\u003E (additional information is provided in the \u003Ca href=\"#S9\"\u003ESupplementary Table S2\u003C\u002Fa\u003E). The strains expressing positive activity for all four tested parameters belonged to the genera \u003Ci\u003EPseudomonas\u003C\u002Fi\u003E and \u003Ci\u003EBacillus\u003C\u002Fi\u003E. The ones expressing positive activity for at least three of the parameters tested belonged to the genera \u003Ci\u003EPseudomonas\u003C\u002Fi\u003E, \u003Ci\u003EPantoea\u003C\u002Fi\u003E, \u003Ci\u003EInquilinus\u003C\u002Fi\u003E, \u003Ci\u003ERhizobium\u003C\u002Fi\u003E, and \u003Ci\u003EBacillus\u003C\u002Fi\u003E. On the other hand, bacteria from the genus \u003Ci\u003EStenotrophomonas\u003C\u002Fi\u003E seem to only be able to produce siderophores. The partial 16S sequences of these 127 tested strains are available in GenBank database under the accession numbers MW353471–MW353597 (\u003Ca href=\"#S9\"\u003ESupplementary Table S3\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 2\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"FigureDesc\"\u003E\r\n\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F633488\u002Ffmicb-12-633488-HTML\u002Fimage_m\u002Ffmicb-12-633488-g002.jpg\" name=\"figure2\" target=\"_blank\"\u003E\r\n\u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F633488\u002Ffmicb-12-633488-HTML\u002Fimage_t\u002Ffmicb-12-633488-g002.gif\" id=\"F2\" alt=\"www.frontiersin.org\" \u002F\u003E\u003C\u002Fa\u003E\r\n\u003Cp\u003E\u003Cstrong\u003EFigure 2.\u003C\u002Fstrong\u003E Neighbor-joining phylogenetic tree based on 16S rRNA gene sequences, with Juke-Cantor model, showing the phylogenetic relationships of strains tested \u003Ci\u003Ein vitro\u003C\u002Fi\u003E for plant growth, cell-wall degrading enzymes and susceptibility to the mixture of A\u002FS. Activities detected are shown in the outer circle. Sequences were aligned using 361 CLC Main Workbench 7.9.1 (Qiagen). Subsequently, a phylogenetic maximum-likelihood tree (1000 bootstraps) was reconstructed and visualized using the iTOL software 5.6.3 (\u003Ca href=\"#B43\"\u003ELetunic and Bork, 2019\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Ch3\u003EEnzymatic Activities\u003C\u002Fh3\u003E\r\n\u003Cp class=\"mb0\"\u003EEnzymatic activities of the 127 strains are presented in \u003Ca href=\"#F2\"\u003EFigure 2\u003C\u002Fa\u003E (additional information is provided in \u003Ca href=\"#S9\"\u003ESupplementary Table S2\u003C\u002Fa\u003E). The cellulase activity seemed to be predominant in the \u003Ci\u003ERhizobiaceae\u003C\u002Fi\u003E family, whereas pectinase activity was abundant among the Bacteroidetes phylum. Among the strains tested, some showed two degrading activities: pectinase and ligninolytic activities were detected for R-72191 (\u003Ci\u003EOlivibacter\u003C\u002Fi\u003E sp.), R-72210 (\u003Ci\u003EPseudomonas\u003C\u002Fi\u003E sp.), R-72249 (\u003Ci\u003EPedobacter\u003C\u002Fi\u003E sp.), R-72394 (\u003Ci\u003EPantoea\u003C\u002Fi\u003E sp.), R-72464 (\u003Ci\u003EXanthomonas\u003C\u002Fi\u003E sp.), R-7264, and R-74277 (\u003Ci\u003EBacillus\u003C\u002Fi\u003E sp.); cellulase and pectinase activities for the strain R-71830 (\u003Ci\u003EBrevibacillus\u003C\u002Fi\u003E sp.) and cellulase and ligninolytic activities for R-72157 (\u003Ci\u003ERhizorhapis\u003C\u002Fi\u003E sp.).\u003C\u002Fp\u003E\r\n\u003Ch3\u003ESusceptibility Assay\u003C\u002Fh3\u003E\r\n\u003Cp class=\"mb0\"\u003ESusceptibility to the antimicrobial activity of alkannin and shikonin derivatives (in the form of a mixture of A\u002FS pigments) was studied for the 127 strains tested for PGP and enzymatic activities. A strain was considered as sensitive to A\u002FS derivatives when an inhibition zone of more than 1 mm was observed. An example of the assay is shown in \u003Ca href=\"#F3\"\u003EFigure 3\u003C\u002Fa\u003E. A pattern could be observed in the susceptibility to the A\u002FS mixture (50 μg): all Gram-positive bacteria tested were sensitive whereas the Gram-negative bacteria tested were resistant (\u003Ca href=\"#F2\"\u003EFigure 2\u003C\u002Fa\u003E). No such pattern was observed for ampicillin which was used as a control. As shown in \u003Ca href=\"#F3\"\u003EFigure 3\u003C\u002Fa\u003E, the halos observed as a result of sensitivity to A\u002FS derivatives were always smaller in diameter than those produced as a result of ampicillin sensitivity.\u003C\u002Fp\u003E\r\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 3\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"FigureDesc\"\u003E\r\n\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F633488\u002Ffmicb-12-633488-HTML\u002Fimage_m\u002Ffmicb-12-633488-g003.jpg\" name=\"figure3\" target=\"_blank\"\u003E\r\n\u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F633488\u002Ffmicb-12-633488-HTML\u002Fimage_t\u002Ffmicb-12-633488-g003.gif\" id=\"F3\" alt=\"www.frontiersin.org\" \u002F\u003E\u003C\u002Fa\u003E\r\n\u003Cp\u003E\u003Cstrong\u003EFigure 3.\u003C\u002Fstrong\u003E Susceptibility of strain R-72492 (\u003Ci\u003EBacillus\u003C\u002Fi\u003E sp.) to the mixture of alkannin\u002Fshikonin derivatives isolated from \u003Ci\u003EAlkanna tinctoria\u003C\u002Fi\u003E roots.\u003C\u002Fp\u003E\r\n\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Ch3\u003EInduction of A\u002FS Derivatives in Hairy Roots of \u003Ci\u003EA. tinctoria\u003C\u002Fi\u003E\u003C\u002Fh3\u003E\r\n\u003Cp class=\"mb0\"\u003EIn the first screening, treatments with the following bacteria resulted in hairy root extracts showing an OD higher than the control: R-71971 (\u003Ci\u003EBrevibacillus\u003C\u002Fi\u003E sp.), R-72060 (\u003Ci\u003EVariovorax\u003C\u002Fi\u003E sp.), R-72149 (\u003Ci\u003EFilimonas\u003C\u002Fi\u003E sp.), R-72379 (\u003Ci\u003EAllorhizobium\u003C\u002Fi\u003E sp.), R-72395 (\u003Ci\u003EDuganella\u003C\u002Fi\u003E sp.), R-72401 (\u003Ci\u003EShinella\u003C\u002Fi\u003E sp.), R-72406 (\u003Ci\u003EStenotrophomonas\u003C\u002Fi\u003E sp.), R-73072 (\u003Ci\u003EChitinophaga\u003C\u002Fi\u003E sp.), R-74161 (\u003Ci\u003EAcinetobacter\u003C\u002Fi\u003E sp.), and R-75348 (\u003Ci\u003EMicromonospora\u003C\u002Fi\u003E sp.) (\u003Ca href=\"#T2\"\u003ETable 2\u003C\u002Fa\u003E). The seven bacteria resulting in an OD > 0.20 were repeated in five replicates in a second assay. The one-factor ANOVA conducted on the results of the second assay showed that the \u003Ci\u003Ep\u003C\u002Fi\u003E-value = 0.00179 was lower than 0.05. The bacterial treatment had an influence on the A\u002FS content. The comparison made with the test of Newman Keuls are presented \u003Ca href=\"#T3\"\u003ETable 3\u003C\u002Fa\u003E. \u003Ci\u003EChitinophaga\u003C\u002Fi\u003E sp. strain R-73072, \u003Ci\u003EAllorhizobium\u003C\u002Fi\u003E sp. strain R-72379, \u003Ci\u003EMassilia\u003C\u002Fi\u003E sp. strain R-72395, and \u003Ci\u003EMicromonospora\u003C\u002Fi\u003E sp. strain R-75348 induced significantly more A\u002FS derivatives in the hairy roots of \u003Ci\u003EA. tinctoria\u003C\u002Fi\u003E when compared to the uninoculated control.\u003C\u002Fp\u003E\r\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"Imageheaders\"\u003ETABLE 2\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"FigureDesc\"\u003E\r\n\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F633488\u002Ffmicb-12-633488-HTML\u002Fimage_m\u002Ffmicb-12-633488-t002.jpg\" name=\"table2\" target=\"_blank\"\u003E\r\n\u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F633488\u002Ffmicb-12-633488-HTML\u002Fimage_t\u002Ffmicb-12-633488-t002.gif\" id=\"T2\" alt=\"www.frontiersin.org\" \u002F\u003E\u003C\u002Fa\u003E\r\n\u003Cp\u003E\u003Cstrong\u003ETable 2.\u003C\u002Fstrong\u003E Optical density at 520 nm reflecting the total A\u002FS content of hairy roots extracts of \u003Ci\u003EAlkanna tinctoria\u003C\u002Fi\u003E treated with selected bacteria.\u003C\u002Fp\u003E\r\n\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"DottedLine mb15\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"Imageheaders\"\u003ETABLE 3\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"FigureDesc\"\u003E\r\n\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F633488\u002Ffmicb-12-633488-HTML\u002Fimage_m\u002Ffmicb-12-633488-t003.jpg\" name=\"table3\" target=\"_blank\"\u003E\r\n\u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F633488\u002Ffmicb-12-633488-HTML\u002Fimage_t\u002Ffmicb-12-633488-t003.gif\" id=\"T3\" alt=\"www.frontiersin.org\" \u002F\u003E\u003C\u002Fa\u003E\r\n\u003Cp\u003E\u003Cstrong\u003ETable 3.\u003C\u002Fstrong\u003E Comparisons of the OD 520 nm reflecting the total A\u002FS content of hairy roots extracts of \u003Ci\u003EAlkanna tinctoria\u003C\u002Fi\u003E inoculated with the best bacterial candidates with Neuman Keuls test.\u003C\u002Fp\u003E\r\n\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Ca id=\"h5\" name=\"h5\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EDiscussion\u003C\u002Fh2\u003E\r\n\u003Cp class=\"mb15\"\u003EThe cultivation of members of \u003Ci\u003EBoraginaceae\u003C\u002Fi\u003E with strong medicinal value such as \u003Ci\u003EA. tinctoria\u003C\u002Fi\u003E and \u003Ci\u003ELithospermum\u003C\u002Fi\u003E spp. has proven to be difficult. For example, \u003Ci\u003ELithospermum\u003C\u002Fi\u003E spp. germinate poorly and seedlings are highly susceptible to viral infections. Additionally, plants can only be harvested 2–3 years after germination and the in-field maintenance of these plants has also proved to be difficult (\u003Ca href=\"#B85\"\u003EYazaki, 2017\u003C\u002Fa\u003E). Applying suitable endophytes to facilitate plant growth by increasing the plant biomass and\u002For by inducing A\u002FS production can be a sustainable approach toward increasing plant yield and production of these valuable compounds.\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003EAs a first step toward the elucidation of the potential role of root endophytic bacteria in the production for secondary metabolites such as A\u002FS derivatives of \u003Ci\u003EA. tinctoria\u003C\u002Fi\u003E, we isolated and characterized culturable endophytic bacteria from \u003Ci\u003EA. tinctoria\u003C\u002Fi\u003E roots. In total, 197 unique phylotypes were recovered, representing 4 phyla. Also, three potentially new genera and 40 potentially new species were recovered from the roots of wild \u003Ci\u003EA. tinctoria\u003C\u002Fi\u003E plants. Most studies to date involving the isolation of endophytic bacteria typically use one type of isolation medium to cultivate a wide range of microorganisms (e.g., nutrient agar or TSA), a set temperature of 28°C and an incubation time between 48 and 72 h (\u003Ca href=\"#B25\"\u003EGermida et al., 1998\u003C\u002Fa\u003E; \u003Ca href=\"#B50\"\u003EMbai et al., 2013\u003C\u002Fa\u003E; \u003Ca href=\"#B4\"\u003EAnjum and Chandra, 2015\u003C\u002Fa\u003E; \u003Ca href=\"#B70\"\u003ESaini et al., 2015\u003C\u002Fa\u003E). In this study, we showed that a higher diversity of bacteria can be obtained when more than one medium is used. Nutrient-poor media such as R2A or diluted TSA seem better at capturing more diversity than a rich medium such as ISP2 (\u003Ca href=\"#T1\"\u003ETable 1\u003C\u002Fa\u003E and \u003Ca href=\"#S9\"\u003ESupplementary Figure S1\u003C\u002Fa\u003E). The latter is a medium rich in nitrogen and carbon sources and has been designed for the routine cultivation of \u003Ci\u003EStreptomyces\u003C\u002Fi\u003E sp. (\u003Ca href=\"#B74\"\u003EShirling and Gottlieb, 1966\u003C\u002Fa\u003E). However, as it may favor the fast-growing bacteria, it may be less suitable to isolate slow growing ones. R2A medium was designed for slow-growing bacteria (\u003Ca href=\"#B68\"\u003EReasoner and Geldreich, 1985\u003C\u002Fa\u003E) and medium 1\u002F10 869 for endophytes (\u003Ca href=\"#B22\"\u003EEevers et al., 2015\u003C\u002Fa\u003E), whereas TSA medium is non-selective and allows the growth of a wide range of microorganisms (\u003Ca href=\"#B42\"\u003ELeavitt et al., 1958\u003C\u002Fa\u003E). The dilution of TSA increased the growth of slow-growing bacteria when compared to the non-diluted medium. Changes in the quantity and the quality of the carbon source and the nature of electrons donors (e.g., succinate, butyrate, acetate) and acceptors (HEPES solution; \u003Ca href=\"#B38\"\u003EKöpke et al., 2005\u003C\u002Fa\u003E), as well as the addition of supplements like enzymes or antibiotics to isolation media are known to generate higher microbial diversity (\u003Ca href=\"#B3\"\u003EAlain and Querellou, 2009\u003C\u002Fa\u003E). For example, the nitrogen sources of TSA medium are casein and peptones whereas R2A and 869 media contain yeast extract. Moreover, TSA does not have additional carbon sources such as glucose. Poor media limit the risk that fast-growing bacteria eliminate those that grow slower by outcompeting them for nutrients or by negatively affecting the growth conditions (pH or the production of metabolites). Critically, slow-growers or species that grow poorly \u003Ci\u003Ein vitro\u003C\u002Fi\u003E may be naturally abundant in planta (\u003Ca href=\"#B3\"\u003EAlain and Querellou, 2009\u003C\u002Fa\u003E; \u003Ca href=\"#B39\"\u003EKram and Finkel, 2015\u003C\u002Fa\u003E). Lower temperature and longer incubation time were also more suited to recovering gram-positive bacteria such as Actinobacteria. Indeed, studies focusing on Actinobacteria demonstrated that an incubation period of 3–4 weeks was necessary for their isolation (\u003Ca href=\"#B6\"\u003EAraújo et al., 2000\u003C\u002Fa\u003E; \u003Ca href=\"#B19\"\u003ECoombs and Franco, 2003\u003C\u002Fa\u003E; \u003Ca href=\"#B51\"\u003EMisk and Franco, 2011\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003EWhile the isolation conditions are important determining factors for the recovery of bacterial isolates, the diversity observed here between different roots (\u003Ca href=\"#F1\"\u003EFigure 1\u003C\u002Fa\u003E and \u003Ca href=\"#S9\"\u003ESupplementary Figure S2\u003C\u002Fa\u003E) indicates that other factors are also important. For example, no Gammaproteobacteria such as \u003Ci\u003EPseudomonas\u003C\u002Fi\u003E sp., \u003Ci\u003EXanthomonas\u003C\u002Fi\u003E sp., or \u003Ci\u003EPantoea\u003C\u002Fi\u003E sp. seemed to be present in one of the root samples (\u003Ca href=\"#F1\"\u003EFigure 1\u003C\u002Fa\u003E). Bacterial isolation results can be biased by the origin and storage conditions of the biological sample or the colony picking method, in addition to the isolation conditions, which may have contributed to the variation in phylotype distribution observed between roots and isolation campaigns (\u003Ca href=\"#S9\"\u003ESupplementary Figure S2\u003C\u002Fa\u003E). We studied wild-collected plants from different locations and therefore, parameters such as the genetics of the plant (\u003Ca href=\"#B28\"\u003EHaney et al., 2015\u003C\u002Fa\u003E), local soil composition (\u003Ca href=\"#B44\"\u003ELiu et al., 2019\u003C\u002Fa\u003E), or the presence of neighboring plants (\u003Ca href=\"#B72\"\u003ESchlatter et al., 2015\u003C\u002Fa\u003E; \u003Ca href=\"#B23\"\u003EEssarioui et al., 2016\u003C\u002Fa\u003E) might also influence the diversity of bacteria recovered. Microbiome analysis as well as the study of the growth conditions of the plant in its natural environment might shed light on bacterial variation between samples.\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003EThe endophytic bacteria found in most of the root samples were tested for a number of plant-growth promotion (PGP) characteristics. The most interesting species for plant growth promoting activity belong to the genera \u003Ci\u003EPseudomonas\u003C\u002Fi\u003E, \u003Ci\u003EPantoea\u003C\u002Fi\u003E, \u003Ci\u003EInquilinu\u003C\u002Fi\u003Es, \u003Ci\u003ERhizobium\u003C\u002Fi\u003E, and \u003Ci\u003EBacillus\u003C\u002Fi\u003E (\u003Ca href=\"#F2\"\u003EFigure 2\u003C\u002Fa\u003E, \u003Ca href=\"#S9\"\u003ESupplementary Table S2\u003C\u002Fa\u003E). Members of these genera were recovered on all media used for isolation. The ability to grow easily \u003Ci\u003Ein vitro\u003C\u002Fi\u003E is promising for their application as plant growth promoting rhizobacteria (PGPRs). Some bacteria showed variable results were obtained from the ACC deaminase test (\u003Ca href=\"#S9\"\u003ESupplementary Table S2\u003C\u002Fa\u003E). These bacteria were colored and\u002For were prone to form biofilms or clumps which can lead inaccurate spectrophotometric readings. To overcome this issue, quantitative analysis might be applied by measuring the amount of α-ketobutyrate at 540 nm (\u003Ca href=\"#B63\"\u003EPenrose and Glick, 2003\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003EMoreover, several bacteria produced \u003Ci\u003Ein vitro\u003C\u002Fi\u003E cell-wall degrading enzymes such as cellulases, pectinases and ligninases. These properties facilitate bacterial entry and spread within the plant tissues and may contribute to the endophytic lifestyle of these bacteria. Strains belonging to \u003Ci\u003EPseudomonas\u003C\u002Fi\u003E sp., \u003Ci\u003EPantoea\u003C\u002Fi\u003E sp., \u003Ci\u003ERhizobium\u003C\u002Fi\u003E sp., and \u003Ci\u003EBacillus\u003C\u002Fi\u003E sp. expressing PGP and enzymatic activities (\u003Ca href=\"#F2\"\u003EFigure 2\u003C\u002Fa\u003E and \u003Ca href=\"#S9\"\u003ESupplementary Table S2\u003C\u002Fa\u003E) might thus show stronger impact on plant growth or A\u002FS induction due to their ability to actively colonize the plant.\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003EThe resistance assay demonstrated that Gram-negative bacteria are resistant to the antimicrobial properties of A\u002FS derivatives (\u003Ca href=\"#F2\"\u003EFigure 2\u003C\u002Fa\u003E and \u003Ca href=\"#S9\"\u003ESupplementary Table S2\u003C\u002Fa\u003E). Although the activity of A\u002FS derivatives at 50 μg seemed weak, the experiment confirmed the antimicrobial properties of these naphthoquinones. The antimicrobial activity of A\u002FS has been linked to their ability to form semiquinone radicals by interacting with reactive oxygen species. They can generate endogenous superoxide anion radicals, resulting in their cytotoxicity (\u003Ca href=\"#B60\"\u003EPapageorgiou et al., 2008\u003C\u002Fa\u003E, \u003Ca href=\"#B61\"\u003E1999\u003C\u002Fa\u003E; \u003Ca href=\"#B57\"\u003EOrdoudi et al., 2011\u003C\u002Fa\u003E). The peptidoglycan cell wall of the Gram-positive bacteria is permeable to molecules with molecular weights in the range of 30,000–57,000 Da, and hence allows for the entry of many small antimicrobials which may partially explain their sensitivity (\u003Ca href=\"#B41\"\u003ELambert, 2002\u003C\u002Fa\u003E). On the other hand, several mechanisms might be involved in the resistance of the Gram-negative bacteria to A\u002FS, especially through redox processes. Chemical and transcriptomic analyses may provide a better understanding of the processes involved. Most of the bacteria having a positive effect in the \u003Ci\u003Ein vitro\u003C\u002Fi\u003E plant growth promoting activities tested were Gram-negative and thus resistant to A\u002FS derivatives. This resistance may provide a competitive advantage for colonizing the plant and living in the root tissues. Consequently, the plant may select for plant growth promoting bacteria through the production of A\u002FS derivatives. Alternatively, sensitive bacteria may colonize the plant shortly after germination when the A\u002FS derivatives content is low or they may be present in the seed and are vertically transmitted (\u003Ca href=\"#B81\"\u003ETruyens et al., 2014\u003C\u002Fa\u003E). In the future, these hypotheses might be tested by inoculating isolates that are sensitive to A\u002FS at different plant growth stages and by tracking their presence and abundance within the plant, thus establishing whether or not these strains can colonize and survive in the plant or not.\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003EStudies have shown that in the hairy roots of \u003Ci\u003EA. tinctoria\u003C\u002Fi\u003E, A\u002FS derivatives are produced by root border cells of the growing root tips. They are then sequestered as lipid granules in the phospholipid layer of these cells and accumulate in apoplastic spaces. However, how the A\u002FS derivatives are secreted into the environment still remains unclear. Nevertheless, it is known that this process results from plant stress and involves the actin filaments (\u003Ca href=\"#B17\"\u003EBrigham et al., 1999\u003C\u002Fa\u003E; \u003Ca href=\"#B79\"\u003ETatsumi et al., 2016\u003C\u002Fa\u003E). Depending on where the bacteria colonize the plant, it is possible that they do not come into contact with A\u002FS derivatives. Colonization assays can provide insights into the relationship between plant individuals and bacteria in the presence of alkannins and shikonins. Moreover, it has been shown that ethylene regulates the colonization of plant tissue by bacteria: the absence of ethylene in a plant or the addition of an ethylene inhibitor leads to a higher degree of colonization. Bacteria that are able to affect the ethylene level are more competent at colonizing plants (\u003Ca href=\"#B29\"\u003EHardoim et al., 2008\u003C\u002Fa\u003E; \u003Ca href=\"#B45\"\u003ELiu et al., 2017\u003C\u002Fa\u003E). The modulation of plant ethylene levels by bacteria can occur by cleavage of 1-aminocyclopropane-1-carboxylate (ACC), a precursor of ethylene or by inhibiting ACC synthase and\u002For β-cystathionase, both being enzymes involved in the ethylene biosynthesis pathway (\u003Ca href=\"#B29\"\u003EHardoim et al., 2008\u003C\u002Fa\u003E; \u003Ca href=\"#B45\"\u003ELiu et al., 2017\u003C\u002Fa\u003E). To confirm whether bacteria can effectively colonize and positively affect the plant growth and the total A\u002FS content, in planta tests must be performed.\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003E\u003Ci\u003EChitinophaga\u003C\u002Fi\u003E sp. strain R-73072, \u003Ci\u003EAllorhizobium\u003C\u002Fi\u003E sp. strain R-72379, \u003Ci\u003EMassilia\u003C\u002Fi\u003E sp. strain R-72395, and \u003Ci\u003EMicromonospora\u003C\u002Fi\u003E sp. strain R-75348 showed the ability to directly induce A\u002FS production in \u003Ci\u003EA. tinctoria\u003C\u002Fi\u003E hairy root cultures. Hairy roots are genetically modified plant material (\u003Ca href=\"#B27\"\u003EGutierrez-Valdes et al., 2020\u003C\u002Fa\u003E). The use of MS + 1% sucrose medium, which is a poor medium for bacterial culture, as well as the presence of agitation, might affect the ability of the bacteria to colonize the roots or their abilities to produce biofilm and\u002For metabolites. During plant colonization, the production of bacterial enzymes or metabolites may induce the production of A\u002FS derivatives by the plant. Our hairy root system served as a general screening tool and may be not optimized for specific plant-bacteria interactions. It might therefore underestimate the number of A\u002FS inducers. Nonetheless, \u003Ci\u003Ein vitro\u003C\u002Fi\u003E whole plant systems usually employ growth medium similar to MS (\u003Ca href=\"#B64\"\u003EPhillips and Garda, 2019\u003C\u002Fa\u003E) and therefore bacteria showing inducing properties in hairy roots can likely induce A\u002FS \u003Ci\u003Ein vitro\u003C\u002Fi\u003E plant system. The bacterial strains R-73072, R-72379, and R-72395 inducing A\u002FS in our system, expressed cell-wall degrading enzymatic activities (pectinase or ligninase) \u003Ci\u003Ein vitro\u003C\u002Fi\u003E. Competent endophytes are able to release cell wall degrading enzymes such as cellulases, xylanases, pectinases, and endoglucanases, which facilitate bacterial entry and spread within the plant tissues (\u003Ca href=\"#B34\"\u003EKandel et al., 2017\u003C\u002Fa\u003E; \u003Ca href=\"#B65\"\u003EPinski et al., 2019\u003C\u002Fa\u003E). Nonetheless, colonization remains an invasive process and thus might induce plant defense response, resulting in the synthesis of plant antimicrobials. Alkannin and shikonin derivatives show antimicrobial activities and can thus be considered as plant defense compounds.\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003EAlthough R-75348 did not show any cell-wall degrading activities \u003Ci\u003Ein vitro\u003C\u002Fi\u003E, several studies have demonstrated that \u003Ci\u003EMicromonospora\u003C\u002Fi\u003E species do have a role in the breakdown of plant cell walls through the production of hydrolytic enzymes (\u003Ca href=\"#B30\"\u003EHirsch and Valdés, 2010\u003C\u002Fa\u003E; \u003Ca href=\"#B80\"\u003ETrujillo et al., 2015\u003C\u002Fa\u003E). Our test conditions may not have been suitable for this strain. Alternatively, genome analysis might reveal the presence of such enzymes. Moreover, \u003Ci\u003EMicromonospora\u003C\u002Fi\u003E sp. is also known to produce antibiotics (\u003Ca href=\"#B15\"\u003EBoumehira et al., 2016\u003C\u002Fa\u003E). Inducing the production of A\u002FS derivatives may depend on plant-bacteria communication through such metabolites. Indeed, some molecules are described as antibiotics because of their effect on microorganisms under \u003Ci\u003Ein vitro\u003C\u002Fi\u003E conditions although their function in the natural habitat can be different. Such molecules can play a role in plant-microbe interactions but can also act as Microbe-Associated Molecular Patterns (MAMPs). MAMPs are resistance-inducing stimuli recognized by specific plant receptors (\u003Ca href=\"#B37\"\u003EKöhl et al., 2019\u003C\u002Fa\u003E). They can also induce pathways involved in plant defense responses.\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003EWe hypothesize that the endophyte’s production of cell-wall degrading enzymes and\u002For secondary metabolites during plant colonization may cause a plant stress resulting in the production of alkannin and shikonin derivatives.\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb0\"\u003EThis study demonstrated the importance of the isolation conditions for the diversity of endophytic isolates recovered from plant roots of \u003Ci\u003EA. tinctoria\u003C\u002Fi\u003E. Nutrient-poor isolation media coupled with an incubation temperature of 20°C and an incubation period of a minimum of 2 weeks allowed for a recovery of a high diversity of culturable endophytic bacteria from \u003Ci\u003EA. tinctoria\u003C\u002Fi\u003E. Although these findings should be validated in greenhouse or field conditions, the positive \u003Ci\u003Ein vitro\u003C\u002Fi\u003E results found regarding potential plant growth promotion features suggest that some of these bacteria might be valuable for future in planta applications. These can be of agronomical interest to boost biomass production or crop yield. Such endophytes also have the potential to increase the yield of secondary metabolites such as A\u002FS derivatives from these medicinal plants by increasing the total biomass. As demonstrated in our study, certain endophytes can also induce A\u002FS production in the roots, probably through to the recognition of bacteria by the plant. These findings open-up the perspective of using a combination of endophytes with the potential for plant growth promotion and induction of secondary metabolite production as a sustainable approach toward increasing the production of secondary metabolites in selected medicinal plants.\u003C\u002Fp\u003E\r\n\u003Ca id=\"h6\" name=\"h6\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EData Availability Statement\u003C\u002Fh2\u003E\r\n\u003Cp class=\"mb0\"\u003EThe datasets presented in this study can be found in online repositories. The names of the repository\u002Frepositories and accession number(s) can be found in the article\u002F\u003Ca href=\"#S9\"\u003ESupplementary Material\u003C\u002Fa\u003E.\u003C\u002Fp\u003E\r\n\u003Ca id=\"h7\" name=\"h7\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EAuthor Contributions\u003C\u002Fh2\u003E\r\n\u003Cp class=\"mb0\"\u003EAW, CS, AAs, and NF designed the study and secured the funding. AR, HN, and AAl designed and performed the experiments. AR analyzed the data and wrote the manuscript. All authors edited, proofread, and approved the manuscript.\u003C\u002Fp\u003E\r\n\u003Ca id=\"fun1\" name=\"fun1\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EFunding\u003C\u002Fh2\u003E\r\n\u003Cp class=\"mb0\"\u003EThis project (Micrometabolite) has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie grant agreement no. 721635.\u003C\u002Fp\u003E\r\n\u003Ca id=\"conf1\" name=\"conf1\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EConflict of Interest\u003C\u002Fh2\u003E\r\n\u003Cp class=\"mb0\"\u003EThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003C\u002Fp\u003E\r\n\u003Ca id=\"ack1\" name=\"ack1\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EAcknowledgments\u003C\u002Fh2\u003E\r\n\u003Cp class=\"mb0\"\u003EWe would like to thank our colleague Stephanie Fordeyn for language advise and proofreading of the manuscript.\u003C\u002Fp\u003E\r\n\u003Ca id=\"S9\" name=\"S9\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003ESupplementary Material\u003C\u002Fh2\u003E\r\n\u003Cp class=\"mb0\"\u003EThe Supplementary Material for this article can be found online at: \u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Farticles\u002F10.3389\u002Ffmicb.2021.633488\u002Ffull#supplementary-material\"\u003Ehttps:\u002F\u002Fwww.frontiersin.org\u002Farticles\u002F10.3389\u002Ffmicb.2021.633488\u002Ffull#supplementary-material\u003C\u002Fa\u003E\u003C\u002Fp\u003E\r\n\u003Ca id=\"refer1\" name=\"refer1\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EReferences\u003C\u002Fh2\u003E\r\n\u003Cdiv class=\"References\" style=\"margin-bottom:0.5em;\"\u003E\r\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B1\" id=\"B1\"\u003E\u003C\u002Fa\u003EAbd_Allah, E. 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Plant Sci.\u003C\u002Fi\u003E 9:1896. doi: 10.3389\u002Ffpls.2018.01896\u003C\u002Fp\u003E\r\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F30619438\" target=\"_blank\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.3389\u002Ffpls.2018.01896\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?&title=The+role+of+host+genetic+signatures+on+root–microbe+interactions+in+the+rhizosphere+and+endosphere%2E&journal=Front%2E+Plant+Sci%2E&author=Yu+P.&author=Hochholdinger+F.&publication_year=2018&volume=9&issue=1896\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\r\n\u003C\u002Fdiv\u003E\r\n\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"thinLineM20\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"AbstractSummary\"\u003E\r\n\u003Cp\u003E\u003Cspan\u003EKeywords\u003C\u002Fspan\u003E: endophytes, isolation, \u003Ci\u003EAlkanna tinctoria\u003C\u002Fi\u003E, alkannin, shikonin, hairy roots\u003C\u002Fp\u003E\r\n\u003Cp\u003E\u003Cspan\u003ECitation:\u003C\u002Fspan\u003E Rat A, Naranjo HD, Krigas N, Grigoriadou K, Maloupa E, Alonso AV, Schneider C, Papageorgiou VP, Assimopoulou AN, Tsafantakis N, Fokialakis N and Willems A (2021) Endophytic Bacteria From the Roots of the Medicinal Plant \u003Ci\u003EAlkanna tinctoria\u003C\u002Fi\u003E Tausch (\u003Ci\u003EBoraginaceae\u003C\u002Fi\u003E): Exploration of Plant Growth Promoting Properties and Potential Role in the Production of Plant Secondary Metabolites. \u003Ci\u003EFront. Microbiol.\u003C\u002Fi\u003E 12:633488. doi: 10.3389\u002Ffmicb.2021.633488\u003C\u002Fp\u003E\r\n\u003Cp id=\"timestamps\"\u003E\r\n\u003Cspan\u003EReceived:\u003C\u002Fspan\u003E 25 November 2020; \u003Cspan\u003EAccepted:\u003C\u002Fspan\u003E 13 January 2021;\u003Cbr\u002F\u003E\u003Cspan\u003EPublished:\u003C\u002Fspan\u003E 03 February 2021.\u003C\u002Fp\u003E\r\n\u003Cdiv\u003E\r\n\u003Cp\u003EEdited by:\u003C\u002Fp\u003E\r\n\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F476457\u002Foverview\"\u003EAleksa Obradović\u003C\u002Fa\u003E, University of Belgrade, Serbia\u003C\u002Fdiv\u003E\r\n\u003Cdiv\u003E\r\n\u003Cp\u003EReviewed by:\u003C\u002Fp\u003E\r\n\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F360397\u002Foverview\"\u003ECarolina Chiellini\u003C\u002Fa\u003E, Italian National Research Council, Italy\u003Cbr\u002F\u003E\r\n\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F549870\u002Foverview\"\u003EDebdulal Banerjee\u003C\u002Fa\u003E, Vidyasagar University, India\u003C\u002Fdiv\u003E\r\n\u003Cp\u003E\u003Cspan\u003ECopyright\u003C\u002Fspan\u003E © 2021 Rat, Naranjo, Krigas, Grigoriadou, Maloupa, Alonso, Schneider, Papageorgiou, Assimopoulou, Tsafantakis, Fokialakis and Willems. This is an open-access article distributed under the terms of the \u003Ca rel=\"license\" href=\"http:\u002F\u002Fcreativecommons.org\u002Flicenses\u002Fby\u002F4.0\u002F\" target=\"_blank\"\u003ECreative Commons Attribution License (CC BY)\u003C\u002Fa\u003E. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\u003C\u002Fp\u003E\r\n\u003Cp\u003E\u003Cspan\u003E*Correspondence:\u003C\u002Fspan\u003E Angélique Rat, \u003Ca href=\"mailto:angelique.rat@ugent.be\"\u003Eangelique.rat@ugent.be\u003C\u002Fa\u003E\u003C\u002Fp\u003E\r\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\r\n\u003C\u002Fdiv\u003E",menuHtml:"\u003Cul class=\"flyoutJournal\"\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h1\"\u003EAbstract\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h2\"\u003EIntroduction\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h3\"\u003EMaterials and Methods\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h4\"\u003EResults\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h5\"\u003EDiscussion\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h6\"\u003EData Availability Statement\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h7\"\u003EAuthor Contributions\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#fun1\"\u003EFunding\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#conf1\"\u003EConflict of Interest\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#ack1\"\u003EAcknowledgments\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#S9\"\u003ESupplementary Material\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#refer1\"\u003EReferences\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003C\u002Ful\u003E\r\n"},files:[{name:"EPUB.epub",fileServerPackageEntryId:e,type:{code:aN,name:aN}},{name:aO,fileServerPackageEntryId:"fmicb-12-633488\u002Ffmicb-12-633488.pdf",type:{code:r,name:r}},{name:aO,fileServerPackageEntryId:e,type:{code:r,name:r}},{name:"fmicb-12-633488.xml",fileServerPackageEntryId:"fmicb-12-633488\u002Ffmicb-12-633488.xml",type:{code:"NLM_XML",name:"XML"}},{name:"Provisional PDF.pdf",fileServerPackageEntryId:e,type:{code:r,name:r}}]},currentArticlePageMetaInfo:{title:aP,link:[{rel:"canonical",href:aQ}],meta:[{hid:x,property:x,name:x,content:aR},{hid:aS,property:aS,name:"title",content:aP},{hid:aT,property:aT,name:x,content:aR},{hid:aU,name:aU,content:"Endophytes,Isolation,Alkanna tinctoria,Alkannin,Shikonin,hairy roots (Min5- Max 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Microbiol.","1664-302X",void 0,18,"Laboratory of Microbiology, Department Biochemistry and Microbiology, Faculty Sciences, Ghent University","Belgium","Laboratory of Conservation and Evaluation of Native and Floricultural Species, Institute of Plant Breeding and Genetic Resources, Hellenic Agricultural Organization Demeter",12,"Laboratory of Microbiology, Department Biochemistry and Microbiology, Faculty Sciences, Ghent University, Belgium","Laboratory of Conservation and Evaluation of Native and Floricultural Species, Institute of Plant Breeding and Genetic Resources, Hellenic Agricultural Organization Demeter, Greece",1920,"por-journal.com",7,"escubed.org",1918,"fipp","https:\u002F\u002Fd2csxpduxe849s.cloudfront.net\u002Fmedia\u002FE32629C6-9347-4F84-81FEAEF7BFA342B3\u002FD7C8E8F5-EB21-4B26-BE7D25D7B2089254\u002Fwebimage-9F239CC8-42C5-479C-ADDCDB2931B331FF.png","image","2022-06-27T10:00:07Z",1440,"fmicb",51,"journal_field","10.3389\u002Ffmicb.2021.633488","Endophytic Bacteria From the Roots of the Medicinal Plant Alkanna tinctoria Tausch (Boraginaceae): Exploration of Plant Growth Promoting Properties and Potential Role in the Production of Plant Secondary Metabolites","\u003Cp\u003EAlkannin and shikonin (A\u002FS) are enantiomeric naphthoquinones produced in the roots of certain plants from the Boraginaceae family such as \u003Citalic\u003ELithospermum\u003C\u002Fitalic\u003E spp. and \u003Citalic\u003EAlkanna\u003C\u002Fitalic\u003E spp. They possess antimicrobial, anti-tumoral and wound healing properties. The production of secondary metabolites by \u003Citalic\u003EAlkanna tinctoria\u003C\u002Fitalic\u003E might be influenced by its endomicrobiome. To study the interaction between this medicinal plant and its bacterial endophytes, we isolated bacteria from the roots of wild growing \u003Citalic\u003EAlkanna tinctoria\u003C\u002Fitalic\u003E collected near to Athens and Thessaloniki in Greece. Representative strains selected by MALDI-TOF mass spectrometry were identified by partial 16S rRNA gene sequence analysis. In total, 197 distinct phylotypes of endophytic bacteria were detected. The most abundant genera recovered were \u003Citalic\u003EPseudomonas\u003C\u002Fitalic\u003E, \u003Citalic\u003EXanthomonas\u003C\u002Fitalic\u003E, \u003Citalic\u003EVariovorax\u003C\u002Fitalic\u003E, \u003Citalic\u003EBacillus\u003C\u002Fitalic\u003E, \u003Citalic\u003EInquilinus\u003C\u002Fitalic\u003E, \u003Citalic\u003EPantoea\u003C\u002Fitalic\u003E, and \u003Citalic\u003EStenotrophomonas\u003C\u002Fitalic\u003E. Several bacteria were then tested \u003Citalic\u003Ein vitro\u003C\u002Fitalic\u003E for their plant growth promoting activity and the production of cell-wall degrading enzymes. Strains of \u003Citalic\u003EPseudomonas\u003C\u002Fitalic\u003E, \u003Citalic\u003EPantoea\u003C\u002Fitalic\u003E, \u003Citalic\u003EBacillus\u003C\u002Fitalic\u003E and \u003Citalic\u003EInquilinus\u003C\u002Fitalic\u003E showed positive plant growth properties whereas those of Bacteroidetes and \u003Citalic\u003ERhizobiaceae\u003C\u002Fitalic\u003E showed pectinase and cellulase activity \u003Citalic\u003Ein vitro\u003C\u002Fitalic\u003E. In addition, bacterial responses to alkannin and shikonin were investigated through resistance assays. Gram negative bacteria were found to be resistant to the antimicrobial properties of A\u002FS, whereas the Gram positives were sensitive. A selection of bacteria was then tested for the ability to induce A\u002FS production in hairy roots culture of \u003Citalic\u003EA. tinctoria\u003C\u002Fitalic\u003E. Four strains belonging to \u003Citalic\u003EChitinophaga\u003C\u002Fitalic\u003E sp., \u003Citalic\u003EAllorhizobium\u003C\u002Fitalic\u003E sp., \u003Citalic\u003EDuganella\u003C\u002Fitalic\u003E sp., and \u003Citalic\u003EMicromonospora\u003C\u002Fitalic\u003E sp., resulted in significantly more A\u002FS in the hairy roots than the uninoculated control. As these bacteria can produce cell-wall degrading enzymes, we hypothesize that the A\u002FS induction may be related with the plant-bacteria interaction during colonization.\u003C\u002Fp\u003E",1152558,"Ang茅lique",1153085,"Henry D.",389080,"Nikos","Katerina",1178870,"Eleni",1205578,"Alicia Varela","Institut f眉r Pflanzenkultur","Germany",76144,"Carolin","Vassilios P.","Organic Chemistry Laboratory, School of Chemical Engineering, Aristotle University of Thessaloniki and Center of Interdisciplinary Research and Innovation of AUTh (CIRI-AUTh), Natural Products Research Centre of Excellence (NatPro-AUTH)",1178735,"Andreana N.","Nikolaos","Division of Pharmacognosy and Natural Products Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens",132946,"Nikolas",282149,"Anne",476457,"Aleksa",360397,"Carolina",549870,"Debdulal",{},1900,"Microbe and Virus Interactions with Plants","microbe-and-virus-interactions-with-plants",2359,"EPUB","fmicb-12-633488.pdf","Frontiers | Endophytic Bacteria From the Roots of the Medicinal Plant Alkanna tinctoria Tausch (Boraginaceae): Exploration of Plant Growth Promoting Properties and Potential Role in the Production of Plant Secondary Metabolites","https:\u002F\u002Fwww.frontiersin.org\u002Fjournals\u002Fmicrobiology\u002Farticles\u002F10.3389\u002Ffmicb.2021.633488\u002Ffull","Alkannin and shikonin (A\u002FS) are enantiomeric naphthoquinones produced in the roots of certain plants from the Boraginaceae family such as Lithospermum spp. a...","og:title","og:description","keywords","og:site_name","og:image","og:type","og:url","twitter:card","citation_volume","citation_journal_title","citation_publisher","citation_journal_abbrev","citation_issn","citation_doi","citation_firstpage","citation_language","citation_title","citation_keywords","citation_abstract","citation_pdf_url","citation_online_date","citation_publication_date","Institut f眉r Pflanzenkultur, Germany","Organic Chemistry Laboratory, School of Chemical 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