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<meta name="ncbi_db" content="books" /><meta name="ncbi_pdid" content="book-part" /><meta name="ncbi_acc" content="NBK280045" /><meta name="ncbi_domain" content="mlprobe" /><meta name="ncbi_report" content="record" /><meta name="ncbi_type" content="fulltext" /><meta name="ncbi_objectid" content="" /><meta name="ncbi_pcid" content="/NBK280045/" /><meta name="ncbi_pagename" content="Discovery of small molecule probe that shows anti-tubercular activity via Mtb bioA (DAPA synthase) enzyme inhibition - Probe Reports from the NIH Molecular Libraries Program - NCBI Bookshelf" /><meta name="ncbi_bookparttype" content="chapter" /><meta name="ncbi_app" content="bookshelf" />
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<title>Discovery of small molecule probe that shows anti-tubercular activity via Mtb bioA (DAPA synthase) enzyme inhibition - Probe Reports from the NIH Molecular Libraries Program - NCBI Bookshelf</title>
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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="Probe Reports from the NIH Molecular Libraries Program [Internet]" /><meta name="citation_title" content="Discovery of small molecule probe that shows anti-tubercular activity via Mtb bioA (DAPA synthase) enzyme inhibition" /><meta name="citation_publisher" content="National Center for Biotechnology Information (US)" /><meta name="citation_date" content="2015/01/16" /><meta name="citation_author" content="Dominick Casalena" /><meta name="citation_author" content="Partha P. Nag" /><meta name="citation_author" content="SaeWoong Park" /><meta name="citation_author" content="Daniel Wilson" /><meta name="citation_author" content="Rahul Edwankar" /><meta name="citation_author" content="Stephen Johnston" /><meta name="citation_author" content="Hanh Le" /><meta name="citation_author" content="Roger Schilling" /><meta name="citation_author" content="Joshua A. Bittker" /><meta name="citation_author" content="Sivaraman Dandapani" /><meta name="citation_author" content="Benito Munoz" /><meta name="citation_author" content="Ran Dai" /><meta name="citation_author" content="Barry C. Finzel" /><meta name="citation_author" content="Dirk Schnappinger" /><meta name="citation_author" content="Courtney Aldrich" /><meta name="citation_author" content="Stuart L. Schreiber" /><meta name="citation_author" content="Michelle Palmer" /><meta name="citation_pmid" content="25834899" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK280045/" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Discovery of small molecule probe that shows anti-tubercular activity via Mtb bioA (DAPA synthase) enzyme inhibition" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="National Center for Biotechnology Information (US)" /><meta name="DC.Contributor" content="Dominick Casalena" /><meta name="DC.Contributor" content="Partha P. Nag" /><meta name="DC.Contributor" content="SaeWoong Park" /><meta name="DC.Contributor" content="Daniel Wilson" /><meta name="DC.Contributor" content="Rahul Edwankar" /><meta name="DC.Contributor" content="Stephen Johnston" /><meta name="DC.Contributor" content="Hanh Le" /><meta name="DC.Contributor" content="Roger Schilling" /><meta name="DC.Contributor" content="Joshua A. Bittker" /><meta name="DC.Contributor" content="Sivaraman Dandapani" /><meta name="DC.Contributor" content="Benito Munoz" /><meta name="DC.Contributor" content="Ran Dai" /><meta name="DC.Contributor" content="Barry C. Finzel" /><meta name="DC.Contributor" content="Dirk Schnappinger" /><meta name="DC.Contributor" content="Courtney Aldrich" /><meta name="DC.Contributor" content="Stuart L. Schreiber" /><meta name="DC.Contributor" content="Michelle Palmer" /><meta name="DC.Date" content="2015/01/16" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK280045/" /><meta name="description" content="Cofactor biosynthetic pathways are a rich source of potential bacterial drug targets because of their essential nature and lack of corresponding mammalian pathways. The genome sequence of Mycobacterium tuberculosis (Mtb) H37Rv, the model virulent laboratory strain, revealed it has the full metabolic potential to synthesize all vitamins and cofactors. Biotin (vitamin H) is the cofactor responsible for activation of carbon dioxide in acyl-CoA carboxylases involved in fatty acid metabolism and pyruvate carboxylase in gluconeogenesis. Biotin biosynthesis is required for survival of Mtb in vitro and in vivo. Moreover, biotin starvation of an Mtb biotin auxotroph led to cell death, which is unusual as most Mtb auxotrophs enter a nonreplicating phase when starved for their given nutrient in vitro. In a recent study, Schnappinger and co-workers have demonstrated, using a phenotypically well-regulated bioA knockdown Mtb mutant, that silencing of bioA (DAPA synthase) after establishing an infection can defeat a chronic infection in a murine model of TB. These genetic studies provide an unprecedented level of validation for a Mtb target and suggest biotin biosynthesis, BioA in particular, represents an extremely attractive target for the development of new antitubercular agents. We report the discovery of a structurally novel small molecule (CID 1245700) that inhibits bioA and demonstrate antitubercular activity in wild type and Mtb strains that conditionally express bioA." /><meta name="og:title" content="Discovery of small molecule probe that shows anti-tubercular activity via Mtb bioA (DAPA synthase) enzyme inhibition" /><meta name="og:type" content="book" /><meta name="og:description" content="Cofactor biosynthetic pathways are a rich source of potential bacterial drug targets because of their essential nature and lack of corresponding mammalian pathways. The genome sequence of Mycobacterium tuberculosis (Mtb) H37Rv, the model virulent laboratory strain, revealed it has the full metabolic potential to synthesize all vitamins and cofactors. Biotin (vitamin H) is the cofactor responsible for activation of carbon dioxide in acyl-CoA carboxylases involved in fatty acid metabolism and pyruvate carboxylase in gluconeogenesis. Biotin biosynthesis is required for survival of Mtb in vitro and in vivo. Moreover, biotin starvation of an Mtb biotin auxotroph led to cell death, which is unusual as most Mtb auxotrophs enter a nonreplicating phase when starved for their given nutrient in vitro. In a recent study, Schnappinger and co-workers have demonstrated, using a phenotypically well-regulated bioA knockdown Mtb mutant, that silencing of bioA (DAPA synthase) after establishing an infection can defeat a chronic infection in a murine model of TB. These genetic studies provide an unprecedented level of validation for a Mtb target and suggest biotin biosynthesis, BioA in particular, represents an extremely attractive target for the development of new antitubercular agents. We report the discovery of a structurally novel small molecule (CID 1245700) that inhibits bioA and demonstrate antitubercular activity in wild type and Mtb strains that conditionally express bioA." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK280045/" /><meta name="og:site_name" content="NCBI Bookshelf" /><meta name="og:image" content="https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-mlprobe-lrg.png" /><meta name="twitter:card" content="summary" /><meta name="twitter:site" content="@ncbibooks" /><meta name="bk-non-canon-loc" content="/books/n/mlprobe/ml406/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK280045/" /><link rel="stylesheet" href="/corehtml/pmc/css/figpopup.css" type="text/css" media="screen" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books.min.css" type="text/css" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books_print.min.css" type="text/css" media="print" /><style type="text/css">p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .first-line-outdent .bk_ref {display: inline} .body-content h2, .body-content .h2 {border-bottom: 1px solid #97B0C8} .body-content h2.inline {border-bottom: none} a.page-toc-label , .jig-ncbismoothscroll a {text-decoration:none;border:0 !important} .temp-labeled-list .graphic {display:inline-block !important} .temp-labeled-list img{width:100%}</style><script type="text/javascript" src="/corehtml/pmc/js/jquery.hoverIntent.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/common.min.js?_=3.18"> </script><script type="text/javascript" src="/corehtml/pmc/js/large-obj-scrollbars.min.js"> </script><script type="text/javascript">window.name="mainwindow";</script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/book-toc.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/books.min.js"> </script><meta name="book-collection" content="NONE" />
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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="Table of Contents Page" href="/books/n/mlprobe/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-mlprobe-lrg.png" alt="Cover of Probe Reports from the NIH Molecular Libraries Program" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>Probe Reports from the NIH Molecular Libraries Program [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK280045_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK280045_dtls__"><div>Bethesda (MD): National Center for Biotechnology Information (US); 2010-.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/mlprobe/">Contents</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/mlprobe/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search this book" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search this book" submit="false" style="padding: 0.1em 0.4em;" /></div></form></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/mlprobe/ml404/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/mlprobe/ml407/" title="Next page in this title">Next ></a></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK280045_"><span class="title" itemprop="name">Discovery of small molecule probe that shows anti-tubercular activity via <i>Mtb</i> bioA (DAPA synthase) enzyme inhibition</span></h1><p class="contrib-group"><span itemprop="author">Dominick Casalena</span>, <span itemprop="author">Partha P. Nag</span>, <span itemprop="author">SaeWoong Park</span>, <span itemprop="author">Daniel Wilson</span>, <span itemprop="author">Rahul Edwankar</span>, <span itemprop="author">Stephen Johnston</span>, <span itemprop="author">Hanh Le</span>, <span itemprop="author">Roger Schilling</span>, <span itemprop="author">Joshua A. Bittker</span>, <span itemprop="author">Sivaraman Dandapani</span>, <span itemprop="author">Benito Munoz</span>, <span itemprop="author">Ran Dai</span>, <span itemprop="author">Barry C. Finzel</span>, <span itemprop="author">Dirk Schnappinger</span>, <span itemprop="author">Courtney Aldrich</span>, <span itemprop="author">Stuart L. Schreiber</span>, and <span itemprop="author">Michelle Palmer</span>.</p><a data-jig="ncbitoggler" href="#__NBK280045_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK280045_ai__"><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Dominick Casalena</span>,<sup>1</sup> <span itemprop="author">Partha P. Nag</span>,<sup>1</sup> <span itemprop="author">SaeWoong Park</span>,<sup>3</sup> <span itemprop="author">Daniel Wilson</span>,<sup>2</sup> <span itemprop="author">Rahul Edwankar</span>,<sup>1</sup> <span itemprop="author">Stephen Johnston</span>,<sup>1</sup> <span itemprop="author">Hanh Le</span>,<sup>1</sup> <span itemprop="author">Roger Schilling</span>,<sup>1</sup> <span itemprop="author">Joshua A. Bittker</span>,<sup>1</sup> <span itemprop="author">Sivaraman Dandapani</span>,<sup>1</sup> <span itemprop="author">Benito Munoz</span>,<sup>1</sup> <span itemprop="author">Ran Dai</span>,<sup>2</sup> <span itemprop="author">Barry C. Finzel</span>,<sup>2</sup> <span itemprop="author">Dirk Schnappinger</span>,<sup>3</sup> <span itemprop="author">Courtney Aldrich</span>,<sup>2</sup> <span itemprop="author">Stuart L. Schreiber</span>,<sup>1</sup> and <span itemprop="author">Michelle Palmer</span><sup>1</sup>.<sup><img src="/corehtml/pmc/pmcgifs/corrauth.gif" alt="corresponding author" /></sup></p><h4>Affiliations</h4><div class="affiliation"><sup>1</sup>
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The Broad Institute Probe Development Center, Cambridge, MA</div><div class="affiliation"><sup>2</sup>
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Department of Medicinal Chemistry, University of Minnesota, 8-174 Weaver-Densford Hall 308 Harvard St. S.E., Minneapolis, MN 55455 USA</div><div class="affiliation"><sup>3</sup>
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Weill Cornell Medical College, Department of Microbiology, 510 East 70th Street, Room A277/A279, New York, NY 10021</div><div class="affiliation"><sup><img src="/corehtml/pmc/pmcgifs/corrauth.gif" alt="corresponding author" /></sup>Corresponding author email:
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<a href="mailto:dev@null" data-email="gro.etutitsnidaorb@anelasac" class="oemail">gro.etutitsnidaorb@anelasac</a></div></div><p class="small">Received: <span itemprop="datePublished">April 15, 2014</span>; Last Update: <span itemprop="dateModified">January 16, 2015</span>.</p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p>Cofactor biosynthetic pathways are a rich source of potential bacterial drug targets because of their essential nature and lack of corresponding mammalian pathways. The genome sequence of <i>Mycobacterium tuberculosis (Mtb)</i> H37Rv, the model virulent laboratory strain, revealed it has the full metabolic potential to synthesize all vitamins and cofactors. Biotin (vitamin H) is the cofactor responsible for activation of carbon dioxide in acyl-CoA carboxylases involved in fatty acid metabolism and pyruvate carboxylase in gluconeogenesis. Biotin biosynthesis is required for survival of <i>Mtb in vitro</i> and <i>in vivo</i>. Moreover, biotin starvation of an <i>Mtb</i> biotin auxotroph led to cell death, which is unusual as most <i>Mtb</i> auxotrophs enter a nonreplicating phase when starved for their given nutrient <i>in vitro</i>. In a recent study, Schnappinger and co-workers have demonstrated, using a phenotypically well-regulated <i>bioA</i> knockdown <i>Mtb</i> mutant, that silencing of <i>bioA</i> (DAPA synthase) after establishing an infection can defeat a chronic infection in a murine model of TB. These genetic studies provide an unprecedented level of validation for a <i>Mtb</i> target and suggest biotin biosynthesis, BioA in particular, represents an extremely attractive target for the development of new antitubercular agents. We report the discovery of a structurally novel small molecule (CID 1245700) that inhibits <i>bioA</i> and demonstrate antitubercular activity in wild type and <i>Mtb</i> strains that conditionally express <i>bioA</i>.</p></div><div class="h2"></div><p><b>Assigned Assay Grant No:</b> R03 MH096537-01</p><p><b>Screening Center Name & PI:</b> Broad institute Probe Development Center, Stuart L. Schreiber, PhD</p><p><b>Chemistry Center Name & PI:</b> Broad institute Probe Development Center, Stuart L. Schreiber, PhD</p><p><b>Assay Submitter & Institution:</b> Courtney Aldrich, PhD / Dirk Schnappinger, PhD, University of Minnesota and Weill Cornell Medical College</p><p><b>PubChem Summary Bioassay Identifier (AID):</b>
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<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623896" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">623896</a></p><div id="ml406.s1"><h2 id="_ml406_s1_">Probe Structure & Characteristics</h2><div id="ml406.f1" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=ML406.&p=BOOKS&id=280045_ml406f1.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK280045/bin/ml406f1.jpg" alt="ML406." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="title">ML406</span></h3></div><div id="ml406.t1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK280045/table/ml406.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml406.t1_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ml406.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID/ML No.</th><th id="hd_h_ml406.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Targets</th><th id="hd_h_ml406.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BioA_IC<sub>50</sub> (μM)<br />[SID, AID]</th><th id="hd_h_ml406.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">WT <i>M. tb</i> (H37Rv) growth inhibition without biotin_IC<sub>50</sub> (μM)<br />[SID, AID]</th><th id="hd_h_ml406.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Anti-Target</th><th id="hd_h_ml406.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Fold Selective<sup><a class="bk_pop" href="#ml406.tfn1">*</a></sup></th></tr></thead><tbody><tr><td headers="hd_h_ml406.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID 1245700<br /><a href="/pcsubstance/?term=ML406[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML406</a></td><td headers="hd_h_ml406.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>BioA</b></td><td headers="hd_h_ml406.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.03<br /><br />[<a href="https://pubchem.ncbi.nlm.nih.gov/substance/164225891" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 164225891</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/743357" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 743357</a>]</td><td headers="hd_h_ml406.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.2<br /><br />[<a href="https://pubchem.ncbi.nlm.nih.gov/substance/164225891" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 164225891</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/743070" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 743070</a>]</td><td headers="hd_h_ml406.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>BioD</b></td><td headers="hd_h_ml406.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100×</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>*</dt><dd><div id="ml406.tfn1"><p class="no_margin">Selectivity = Anti-target IC<sub>50</sub>/Target IC<sub>50</sub></p></div></dd></dl></div></div></div></div><div id="ml406.s2"><h2 id="_ml406_s2_">1. Recommendations for the scientific use of the probes</h2><p><i>Mycobacterium tuberculosis</i> (<i>Mtb</i>), the primary etiological agent of tuberculosis (TB), has plagued mankind for millennia and remains the leading cause of bacterial infectious disease mortality.<a class="bk_pop" href="#ml406.r1">1</a>-<a class="bk_pop" href="#ml406.r3">3</a> Biotin is an essential cofactor in <i>Mtb</i> and required for the establishment and maintenance of a chronic infection. The goal of the project is to discover a small molecule inhibitor of BioA, an enzyme involved in biotin biosynthesis in <i>Mtb</i> that may serve as lead compounds for drug development for TB. Additionally, rapid acting small-molecule inhibitors can be used as tool compounds to reveal mechanistic insights into the biotin-starvation induced death of <i>Mtb</i>, including potential synergistic effects with other therapeutic pathways.</p></div><div id="ml406.s3"><h2 id="_ml406_s3_">2. Materials and Methods</h2><div id="ml406.s4"><h3>Materials and Reagents</h3><ul><li class="half_rhythm"><div>Fluorescent dethiobiotin (Fl-DTB): Synthesized at C. Aldrich lab, University of Minnesota.</div></li><li class="half_rhythm"><div><i>E.coli</i> BioD: bioD gene was PCR amplified from <i>E. coli</i> BL21 (DE3) genomic DNA and cloned into pET28b to introduce an N-terminal HIS tag. Overexpression of BioD was performed in <i>E. coli</i> BL21-CodonPlus (DE3) cells, and purification of the soluble protein was performed via Ni-NTA affinity chromatography to afford 420 mg of BioD per liter of culture.</div></li><li class="half_rhythm"><div><i>M.tuberculosis</i> BioA: <i>bioA</i> gene was PCR amplified from <i>M. tuberculosis</i> H37Rv genomic DNA and cloned into a pET vector to introduce an N-terminal HIS tag then subcloned into pUC18 to create a vector under control of the lac promoter following the strategy described by Mann and Ploux.<sup>13</sup>Overexpression of BioA was performed in <i>E. coli</i> BL21-CodonPlus (DE3)-RP cells, and purification of the soluble protein was performed via Ni-NTA affinity chromatography to afford 1.5 mg of BioA per liter of culture.</div></li><li class="half_rhythm"><div>7-keto-8-aminopelargonic acid (KAPA) HCl: Synthesized by the C. Aldrich lab, at the University of Minnesota in five steps from Boc-L-alanine using several modifications to the described synthetic route by Lucet and co-workers<sup>24</sup> and obtained as the hydrochloride salt in 85% yield and an enantiomeric ratio of 98:2 as determined by chiral derivitization and HPLC analysis.</div></li><li class="half_rhythm"><div>7,8-diaminopelargonic acid (DAPA) stock solution: synthesized by the C. Aldrich lab, University of Minnesota, as described (Vasantkumar, G.R.; Bhor, V.B.; Surolia, A. <i>Syn. Commun.</i> 2007; 37: 2633-2639.)</div></li><li class="half_rhythm"><div><i>Mtb H37Rv</i>, <i>Mtb bioA TetON-1</i>, and <i>Mtb bioA TetON-5</i> have been described in PMID 21980288<sup>8</sup></div></li></ul></div><div id="ml406.s5"><h3>2.1. Assays</h3><div id="ml406.s6"><h4>2.1.1. Primary assay – Coupled fluorescent dethiobiotin displacement assay for BioA inhibition</h4><p>BioA catalyzes the reversible transamination between KAPA and DAPA. In the second step, which is irreversible, BioD catalyzes the ATP-dependent carbonylation of DAPA to provide dethiobiotin (DTB) and this step drives the BioA reaction forward (1A). Dethiobiotin is detected by displacement of the fluorescent dethiobiotin probe (Fl-DTB) from streptavidin resulting in an increase in the fluorescent signal. The essence of the assay lies in the fluorescence quenching of Fl-DTB by streptavidin and restoration of fluorescence upon release from streptavidin. Another critical feature of the assay that enables it to be performed in a continuous format is the rapid reversible binding of dethiobiotin and Fl-DTB as a result of the substantially weaker binding affinities of the molecules for streptavidin (K<sub>d(App)</sub>=9.5 nM), which contrasts with the functionally irreversible binding of biotin. No increase of fluorescent signal indicates inhibition of dethiobiotin synthesis, and a positive result.</p><p>Compounds and controls were added at 10mM in DMSO (7.5nL) to 1536 well assay plates. Substrate (KAPA) solution, target enzyme (BioA and BioD) solutions, and fluorescent probe (Fl-DTB) quenched by streptavidin were added to the compound wells. After 45 minutes the BioA and BioD catalyzed synthesis of dethiobiotin reactions were quenched with EDTA and fluorescence reads were taken on a Viewlux plate reader (Ex 485, Em 530). Primary HTS data were analyzed in Genedata Screener Assay Analyzer. All values were normalized against DMSO treated samples and the positive control (10 μM CHM-1, CID 357860). For the HTS, the average of two replicates was used to rank order activity and to choose compounds for retests. For dose studies, percent (%) activity was determined for each concentration, and the concentration response curves (CRCs) were generated with Genedata Screener's Condoseo software module.</p></div><div id="ml406.s7"><h4>2.1.2. Secondary assay – Coupled fluorescent dethiobiotin displacement assay for BioD inhibition</h4><p>This counter screen identifies compounds that are inhibitors of the downstream enzyme BioD in the biotin synthetic pathway. The assay uses the same fluorescent probe (Fl-DTB) to detect inhibition of dethiobiotin synthesis as the primary screen. Here the BioA enzyme and KAPA substrate are eliminated from the assay. DAPA is introduced as the starting substrate and inhibition of enzyme activity, detected as no increase in fluorescent signal, indicates compound inhibition of the enzyme BioD. Compounds that are active in this assay are eliminated from further studies since they are targeting the downstream enzyme BioD instead of BioA or are possibly fluorescence quenchers.</p><p>Compounds and controls were added at 8-point dose in two fold dilutions from 10 - 0.78 mM in DMSO (7.5 nL) to 1536 well assay plates. Substrate (DAPA) solution, target enzyme (BioD) solution, and fluorescent probe (Fl-DTB) quenched by streptavidin were added to the compound wells. After 45 minutes the BioD catalyzed synthesis of dethiobiotin reactions were quenched with EDTA and fluorescence reads were taken on a Viewlux plate reader (Ex 485, Em 530). All values were normalized against DMSO treated samples and the positive control (EDTA added to positive control wells prior to substrate addition). For dose studies, percent (%) activity was determined for each concentration, and the concentration response curves (CRCs) were generated with Genedata Screener's Condoseo.</p></div><div id="ml406.s8"><h4>2.1.3. Secondary assay – PLP Cofactor Activity counter screen assay</h4><p>In this counter screen assay compound inhibition of the enzyme cofactor Pyridoxal-5′-phosphate (PLP) is determined by monitoring a decrease in NADH absorbance at 340 nm. Aspartate Transaminase (AST), also known as serum glutamic oxaloacetic Transaminase (GOT) or aspartate aminotransferase (ASAT/AAT), facilitates the conversion of aspartate and α-ketoglutarate to oxaloacetate and glutamate. PLP is a co-enzyme to AST in this transamination reaction. Oxaloacetate and NADH are then converted to malate and NAD by the enzyme malate dehydrogenase. The decrease in NADH absorbance at 340 nm is proportionate to AST and PLP cofactor activity. Absorbance readings are taken at time 0 and 10 minutes. Compounds with inhibition activity to the enzyme and PLP cofactor will result in no NADH absorbance decrease in the assay. Compounds that are active in this assay are eliminated from further studies since they display activity against a functionally related PLP-dependent enzyme and are thus unlikely to possess useful selectivity.</p></div><div id="ml406.s9"><h4>2.1.4. Secondary assay – Mammalian cell cytotoxicity assay</h4><p>Cytotoxicity assays are widely used by industry to screen for cytotoxicity in compound libraries. Cytotoxic compounds often yield a false positive result from the initial high-throughput screen and thus need to be filtered out to prevent investing significant time and expense during development of a potential probe.</p><p>Three cell lines representing in-vivo process were chosen for this in-vitro panel:</p><ol><li class="half_rhythm"><div>HepG2, as human liver cells</div></li><li class="half_rhythm"><div>HEK293, as human kidney cells.</div></li><li class="half_rhythm"><div>A549, as a human lung cancer cells.</div></li></ol><p>Compounds identified as active will be toxic to cells at a compound concentration less than 10 μM. Activity in the assay leads to a reduction in cellular ATP levels which correlates with a decreased luminescence signal from the read reagent (CellTiter-Glo) and indicates cytotoxicity. Compounds that exhibit no cytotoxicity at < 20 μM in all cell lines tested will be prioritized for additional studies.</p></div><div id="ml406.s10"><h4>2.1.5. Whole cell growth inhibition (Mycobacterium tuberculosis)</h4><p>We measured to what extent small-molecule inhibitors of the enzyme BioA (7, 8-diaminopelargonic acid synthase) impaired growth of wild-type (WT) <i>Mycobacterium tuberculosis</i> H37Rv (Mtb), Mtb bioA TetON-1 (SD1 strain), and Mtb bioA TetON-5 (SD5 strain). Mtb bioA TetON-1/5 are mutants in which expression of BioA is induced by anhydrotetracycline (atc) (PMID 21980288). In the presence of atc Mtb bioA TetON-1 (SD1 strain) expresses ∼12× more BioA than WT and Mtb bioA TetON-5 (SD5 strain) expresses approximately 5× less BioA than WT. Growth of Mtb bioA TetON-1 and Mtb bioA TetON-5 was analyzed in media that contained atc but was free of biotin. Growth of WT Mtb was analyzed in biotin-free and biotin-containing media.</p><p>Small molecules that impair growth of Mtb specifically due to inhibition of BioA were expected to be only active in biotin-free media and in these media to be most active against Mtb bioA TetON-5 (SD5 strain) and least active against Mtb bioA TetON-1 (SD1 strain).</p></div></div><div id="ml406.s11"><h3>2.2. Probe Chemical Characterization</h3><p>The probe (<a href="/pcsubstance/?term=ML406[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML406</a>) was synthesized as described in <a href="#ml406.s12">Section 2.3</a> and was subsequently analyzed by UPLC, <sup>1</sup>H and high-resolution mass spectrometry. The data obtained from NMR and mass spectroscopy are consistent with the structure of the probe, and UPLC indicates an isolated purity of greater than 95%. The physical properties of the probe <a href="/pcsubstance/?term=ML406[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML406</a> are summarized in <a class="figpopup" href="/books/NBK280045/table/ml406.t2/?report=objectonly" target="object" rid-figpopup="figml406t2" rid-ob="figobml406t2">Table 1</a>. The solubility of <a href="/pcsubstance/?term=ML406[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML406</a> was determined to be 88.0 μM in PBS with 1% (v/v) DMSO (PBS; pH 7.4, 23 °C).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml406t2"><a href="/books/NBK280045/table/ml406.t2/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figml406t2" rid-ob="figobml406t2"><img class="small-thumb" src="/books/NBK280045/table/ml406.t2/?report=thumb" src-large="/books/NBK280045/table/ml406.t2/?report=previmg" alt="Table 1. Summary of Probe Properties Computed from Structure ML406." /></a><div class="icnblk_cntnt"><h4 id="ml406.t2"><a href="/books/NBK280045/table/ml406.t2/?report=objectonly" target="object" rid-ob="figobml406t2">Table 1</a></h4><p class="float-caption no_bottom_margin">Summary of Probe Properties Computed from Structure ML406. </p></div></div><p>The chemical stability of the probe <a href="/pcsubstance/?term=ML406[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML406</a> was confirmed in the presence of PBS pH 7.4 with 1% DMSO. The probe <a href="/pcsubstance/?term=ML406[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML406</a> was added (in triplicate at 1 μM) on six separate plates and allowed to equilibrate at room temperature for 48 hours. At each time point (0, 2, 4, 8, 24, and 48 hours), one plate was removed and an aliquot was taken out from each well and analyzed by UPLC-MS. After 48 h, more than 80% of <a href="/pcsubstance/?term=ML406[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML406</a> remained (<a class="figpopup" href="/books/NBK280045/figure/ml406.f2/?report=objectonly" target="object" rid-figpopup="figml406f2" rid-ob="figobml406f2">Figure 1</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml406f2" co-legend-rid="figlgndml406f2"><a href="/books/NBK280045/figure/ml406.f2/?report=objectonly" target="object" title="Figure 1" class="img_link icnblk_img figpopup" rid-figpopup="figml406f2" rid-ob="figobml406f2"><img class="small-thumb" src="/books/NBK280045/bin/ml406f2.gif" src-large="/books/NBK280045/bin/ml406f2.jpg" alt="Figure 1. Stability of the Probe (ML406, CID 1245700) in PBS Buffer (pH 7.4, 23°C)." /></a><div class="icnblk_cntnt" id="figlgndml406f2"><h4 id="ml406.f2"><a href="/books/NBK280045/figure/ml406.f2/?report=objectonly" target="object" rid-ob="figobml406f2">Figure 1</a></h4><p class="float-caption no_bottom_margin">Stability of the Probe (ML406, CID 1245700) in PBS Buffer (pH 7.4, 23°C). </p></div></div><p>The probe <a href="/pcsubstance/?term=ML406[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML406</a> is stable in human and murine plasma. The stability of the probe was determined by measuring stability in human plasma (>99% remaining) and murine plasma (>89% remaining) after a 5-hour incubation period at 37 °C (<a class="figpopup" href="/books/NBK280045/table/ml406.t3/?report=objectonly" target="object" rid-figpopup="figml406t3" rid-ob="figobml406t3">Table 2</a>). <a href="/pcsubstance/?term=ML406[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML406</a> showed that it was 99% bound in human plasma and 82.6% bound in mouse plasma (<a class="figpopup" href="/books/NBK280045/table/ml406.t3/?report=objectonly" target="object" rid-figpopup="figml406t3" rid-ob="figobml406t3">Table 2</a>). The encouraging outcome from this broad spectrum of stability experiments makes <a href="/pcsubstance/?term=ML406[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML406</a> a valuable probe molecule.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml406t3"><a href="/books/NBK280045/table/ml406.t3/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figml406t3" rid-ob="figobml406t3"><img class="small-thumb" src="/books/NBK280045/table/ml406.t3/?report=thumb" src-large="/books/NBK280045/table/ml406.t3/?report=previmg" alt="Table 2. Plasma Stability and Plasma Protein Binding of ML406 and CID 72836829." /></a><div class="icnblk_cntnt"><h4 id="ml406.t3"><a href="/books/NBK280045/table/ml406.t3/?report=objectonly" target="object" rid-ob="figobml406t3">Table 2</a></h4><p class="float-caption no_bottom_margin">Plasma Stability and Plasma Protein Binding of ML406 and CID 72836829. </p></div></div><p>The probe (<a href="/pcsubstance/?term=ML406[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML406</a>) and analogue CID 72836829 were found to be stable to both human and murine liver microsomes after 1 hour (<a class="figpopup" href="/books/NBK280045/table/ml406.t4/?report=objectonly" target="object" rid-figpopup="figml406t4" rid-ob="figobml406t4">Table 3</a>). The stability of <a href="/pcsubstance/?term=ML406[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML406</a> in mouse liver microsomes may provide the opportunity to test this compound in an <i>in vivo</i> mouse model of TB infection (after determining <i>in vitro</i> ADME/PK properties and dose tolerability) as a proof of concept experiment.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml406t4"><a href="/books/NBK280045/table/ml406.t4/?report=objectonly" target="object" title="Table 3" class="img_link icnblk_img figpopup" rid-figpopup="figml406t4" rid-ob="figobml406t4"><img class="small-thumb" src="/books/NBK280045/table/ml406.t4/?report=thumb" src-large="/books/NBK280045/table/ml406.t4/?report=previmg" alt="Table 3. Liver Microsome Stability of the Probe (ML406, CID 1245700) and analogue CID 72836829." /></a><div class="icnblk_cntnt"><h4 id="ml406.t4"><a href="/books/NBK280045/table/ml406.t4/?report=objectonly" target="object" rid-ob="figobml406t4">Table 3</a></h4><p class="float-caption no_bottom_margin">Liver Microsome Stability of the Probe (ML406, CID 1245700) and analogue CID 72836829. </p></div></div></div><div id="ml406.s12"><h3>2.3. Probe Preparation</h3><p>Probe <a href="/pcsubstance/?term=ML406[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML406</a> was synthesized by the one-step protocol outlined below in <a class="figpopup" href="/books/NBK280045/figure/ml406.f3/?report=objectonly" target="object" rid-figpopup="figml406f3" rid-ob="figobml406f3">Scheme 1</a>. Amidation reaction between benzo[<i>d</i>][1,3]dioxole-5-carboxylic acid and 4-(4-acetylphenyl)piperazin-1-ium 2,2,2-trifluoroacetate in presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) and <i>N</i>-ethyl-<i>N</i>-isopropylpropan-2-amine in dichloromethane resulted the probe 1-(4-(4-(benzo[<i>d</i>][1,3]dioxole-5-carbonyl)piperazin-1-yl)phenyl)ethanone (<a href="/pcsubstance/?term=ML406[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML406</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml406f3" co-legend-rid="figlgndml406f3"><a href="/books/NBK280045/figure/ml406.f3/?report=objectonly" target="object" title="Scheme 1" class="img_link icnblk_img figpopup" rid-figpopup="figml406f3" rid-ob="figobml406f3"><img class="small-thumb" src="/books/NBK280045/bin/ml406f3.gif" src-large="/books/NBK280045/bin/ml406f3.jpg" alt="Scheme 1. Synthesis of the Probe ML406." /></a><div class="icnblk_cntnt" id="figlgndml406f3"><h4 id="ml406.f3"><a href="/books/NBK280045/figure/ml406.f3/?report=objectonly" target="object" rid-ob="figobml406f3">Scheme 1</a></h4><p class="float-caption no_bottom_margin">Synthesis of the Probe ML406. </p></div></div></div></div><div id="ml406.s13"><h2 id="_ml406_s13_">3. Results</h2><div id="ml406.s14"><h3>3.1. Dose Response Curves for Probe</h3><p><a class="figpopup" href="/books/NBK280045/figure/ml406.f4/?report=objectonly" target="object" rid-figpopup="figml406f4" rid-ob="figobml406f4">Figure 2</a>. We identified CID 1245700 from HTS. After several rounds of SAR, the original hit was still found to be optimal and we nominated it as the probe. The re-synthesized sample of the original HTS hit (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/164225891" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 164225891</a>) also demonstrated similar potencies and the dose response curve of the resynthesized sample are shown in <a class="figpopup" href="/books/NBK280045/figure/ml406.f4/?report=objectonly" target="object" rid-figpopup="figml406f4" rid-ob="figobml406f4">Figure 2</a>.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml406f4" co-legend-rid="figlgndml406f4"><a href="/books/NBK280045/figure/ml406.f4/?report=objectonly" target="object" title="Figure 2" class="img_link icnblk_img figpopup" rid-figpopup="figml406f4" rid-ob="figobml406f4"><img class="small-thumb" src="/books/NBK280045/bin/ml406f4.gif" src-large="/books/NBK280045/bin/ml406f4.jpg" alt="Figure 2. CID 1245700 was tested across a range of concentrations up to 10 μM in the primary assay and secondary counter screen, up to 25 μM in mammalian cytotoxicity assays, and up to 50 μM in live Mtb growth assay." /></a><div class="icnblk_cntnt" id="figlgndml406f4"><h4 id="ml406.f4"><a href="/books/NBK280045/figure/ml406.f4/?report=objectonly" target="object" rid-ob="figobml406f4">Figure 2</a></h4><p class="float-caption no_bottom_margin">CID 1245700 was tested across a range of concentrations up to 10 μM in the primary assay and secondary counter screen, up to 25 μM in mammalian cytotoxicity assays, and up to 50 μM in live <i>Mtb</i> growth assay. Concentration response <a href="/books/NBK280045/figure/ml406.f4/?report=objectonly" target="object" rid-ob="figobml406f4">(more...)</a></p></div></div></div><div id="ml406.s15"><h3>3.2. Cellular Activity</h3><p>All growth inhibition assays described in this report are cell-based experiments that measure the activity of compounds against various <i>M. tuberculosis</i> strains. Cytotoxicity was measured against eukaryotic host cells including HEK293, HepG2 and A549 cell lines. A summary of the assays is described in <a href="#ml406.s5">Section 2.1</a>.</p></div><div id="ml406.s16"><h3>3.3. Profiling Assays</h3><p>No profiling assays were conducted.</p></div></div><div id="ml406.s17"><h2 id="_ml406_s17_">4. Discussion</h2><div id="ml406.s18"><h3>4.1. Comparison to Existing Art and How the New Probe is an Improvement</h3><p>Investigation into relevant prior art entailed searching the following databases: SciFinder, Reaxys, ISI Web of Science, PubChem, PubMed, US Patent and Trademark Office (USPTO) PatFT and AppFT, and World Intellectual Property Organization (WIPO) databases. Abstracts were obtained for all references returned including journal articles, patents and other form of public disclosures and were analyzed for relevance to the current project. The searches were performed on December 3, 2013, and the results are current as of that date.</p><p>The literature and patent searches above identified natural product amiclenomycin as a mechanism-based irreversible inhibitor of the enzyme BioA from <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) (<a class="figpopup" href="/books/NBK280045/figure/ml406.f5/?report=objectonly" target="object" rid-figpopup="figml406f5" rid-ob="figobml406f5">Figure 3</a>).<a class="bk_pop" href="#ml406.r1">1</a>-<a class="bk_pop" href="#ml406.r6">6</a> The chemical instability and inaccessibility of amiclenomycin prevent it from serving as a useful tool compound.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml406f5" co-legend-rid="figlgndml406f5"><a href="/books/NBK280045/figure/ml406.f5/?report=objectonly" target="object" title="Figure 3" class="img_link icnblk_img figpopup" rid-figpopup="figml406f5" rid-ob="figobml406f5"><img class="small-thumb" src="/books/NBK280045/bin/ml406f5.gif" src-large="/books/NBK280045/bin/ml406f5.jpg" alt="Figure 3. Amiclenomycin." /></a><div class="icnblk_cntnt" id="figlgndml406f5"><h4 id="ml406.f5"><a href="/books/NBK280045/figure/ml406.f5/?report=objectonly" target="object" rid-ob="figobml406f5">Figure 3</a></h4><p class="float-caption no_bottom_margin">Amiclenomycin. </p></div></div><p>A preliminary validation screen with the LOPAC1280 library conducted in the laboratory of Professor Aldrich (Assay Provider for this project) identified six BioA inhibitors (<a class="figpopup" href="/books/NBK280045/figure/ml406.f6/?report=objectonly" target="object" rid-figpopup="figml406f6" rid-ob="figobml406f6">Figure 4</a>).<a class="bk_pop" href="#ml406.r7">7</a> CHM-1 was the most potent among these inhibitors (IC<sub>50</sub>=0.44μM, MIC<sub>50</sub>=5μM in <i>Mtb</i> under expressing BioA and MIC<sub>50</sub>>200μM in Mtb over expressing BioA). Follow up studies with CHM-1 revealed that, in the absence of biotin, modest activity (MIC<sub>50</sub>=50 μM) against wild-type <i>Mycobacterium tuberculosis</i> H37Rv was observed.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml406f6" co-legend-rid="figlgndml406f6"><a href="/books/NBK280045/figure/ml406.f6/?report=objectonly" target="object" title="Figure 4" class="img_link icnblk_img figpopup" rid-figpopup="figml406f6" rid-ob="figobml406f6"><img class="small-thumb" src="/books/NBK280045/bin/ml406f6.gif" src-large="/books/NBK280045/bin/ml406f6.jpg" alt="Figure 4. Prior Art compounds." /></a><div class="icnblk_cntnt" id="figlgndml406f6"><h4 id="ml406.f6"><a href="/books/NBK280045/figure/ml406.f6/?report=objectonly" target="object" rid-ob="figobml406f6">Figure 4</a></h4><p class="float-caption no_bottom_margin">Prior Art compounds. </p></div></div><p>At this point, <a href="/pcsubstance/?term=ML406[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML406</a> shows superior activity profile across all assays over CHM1.</p></div></div><div id="ml406.s19"><h2 id="_ml406_s19_">5. References</h2><dl class="temp-labeled-list"><dt>1.</dt><dd><div class="bk_ref" id="ml406.r1">Okami Y, Kitahara T, Hamada M, Naganawa H, Kondo S. Studies on a new amino acid antibiotic, amiclinomycin. <span><span class="ref-journal">J. Antibiot. </span>1974;<span class="ref-vol">27</span>:656–664.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/4436150" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 4436150</span></a>]</div></dd><dt>2.</dt><dd><div class="bk_ref" id="ml406.r2">Hotta K, Kitahara T, Okami Y. Studies of the mode of action of amiclinomycin. <span><span class="ref-journal">J. Antibiot. </span>1975;<span class="ref-vol">28</span>:222–228.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/805119" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 805119</span></a>]</div></dd><dt>3.</dt><dd><div class="bk_ref" id="ml406.r3">Poetsch M, Zahner H, Werner RG, Kern A, Jung G. Metabolic products from microorganisms. 230. Amiclinomycin-peptides, new antimetabolites of biotin. <span><span class="ref-journal">J. Antibiot. </span>1985;<span class="ref-vol">38</span>:312–320.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/3891702" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3891702</span></a>]</div></dd><dt>4.</dt><dd><div class="bk_ref" id="ml406.r4">Sandmark J, Mann S, Marquet A, Schneider G. Structural basis for the inhibition of the biosynthesis of biotin by the antibiotic amiclenomycin. <span><span class="ref-journal">J. Biol. Chem. </span>2002;<span class="ref-vol">277</span>:43352–43358.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12218056" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12218056</span></a>]</div></dd><dt>5.</dt><dd><div class="bk_ref" id="ml406.r5">Mann S, Florentin D, Lesage D, Drujon T, Ploux O, Marquet A. Inhibition of Diamino Pelargonic Acid Aminotransferase, an Enzyme of the Biotin Biosynthetic Pathway, by Amiclenomycin: A Mechanistic Study. <span><span class="ref-journal">Helv. Chim. Acta. </span>2003;<span class="ref-vol">86</span>:3836–3850.</span> [<a href="http://dx.crossref.org/10.1002/hlca.200390322" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">CrossRef</a>]</div></dd><dt>6.</dt><dd><div class="bk_ref" id="ml406.r6">Kitahara T, Hotta K, Yoshida M, Okami Y. Biological Studies of amiclinomycin. <span><span class="ref-journal">J. Antibiot. </span>1975;<span class="ref-vol">28</span>:215–221.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/805118" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 805118</span></a>]</div></dd><dt>7.</dt><dd><div class="bk_ref" id="ml406.r7">Wilson DJ, Shi C, Duckworth BP, Muretta JM, Sham YY, Thomas DD, Aldrich CC. A continuous fluorescence displacement assay for BioA: an enzyme involved in biotin biosynthesis. <span><span class="ref-journal">Anal. Biochem. </span>2011;<span class="ref-vol">416</span>:27–38.</span> [<a href="/pmc/articles/PMC3135573/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3135573</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21621502" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21621502</span></a>]</div></dd></dl></div><div id="bk_toc_contnr"></div></div></div>
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<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK280045/?report=reader">PubReader</a></li><li><a href="/books/NBK280045/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK280045" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK280045" style="display:none" title="Cite this Page"><div class="bk_tt">Casalena D, Nag PP, Park SW, et al. Discovery of small molecule probe that shows anti-tubercular activity via Mtb bioA (DAPA synthase) enzyme inhibition. 2014 Apr 15 [Updated 2015 Jan 16]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. <span class="bk_cite_avail"></span></div></div></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>In this Page</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="page-toc" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="#ml406.s1" ref="log$=inpage&link_id=inpage">Probe Structure & Characteristics</a></li><li><a href="#ml406.s2" ref="log$=inpage&link_id=inpage">Recommendations for the scientific use of the probes</a></li><li><a href="#ml406.s3" ref="log$=inpage&link_id=inpage">Materials and Methods</a></li><li><a href="#ml406.s13" ref="log$=inpage&link_id=inpage">Results</a></li><li><a href="#ml406.s17" ref="log$=inpage&link_id=inpage">Discussion</a></li><li><a href="#ml406.s19" ref="log$=inpage&link_id=inpage">References</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related information</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="discovery_db_links" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pmc&DbFrom=books&Cmd=Link&LinkName=books_pmc_refs&IdsFromResult=3412236" ref="log$=recordlinks">PMC</a><div class="brieflinkpop offscreen_noflow">PubMed Central citations</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pcsubstance&DbFrom=books&Cmd=Link&LinkName=books_pcsubstance&IdsFromResult=3412236" ref="log$=recordlinks">PubChem Substance</a><div class="brieflinkpop offscreen_noflow">Related PubChem Substances</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pubmed&DbFrom=books&Cmd=Link&LinkName=books_pubmed_refs&IdsFromResult=3412236" ref="log$=recordlinks">PubMed</a><div class="brieflinkpop offscreen_noflow">Links to PubMed</div></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Similar articles in PubMed</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PBooksDiscovery_RA" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/21980288" ref="ordinalpos=1&linkpos=1&log$=relatedarticles&logdbfrom=pubmed">Evaluating the sensitivity of Mycobacterium tuberculosis to biotin deprivation using regulated gene expression.</a><span class="source">[PLoS Pathog. 2011]</span><div class="brieflinkpop offscreen_noflow">Evaluating the sensitivity of Mycobacterium tuberculosis to biotin deprivation using regulated gene expression.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Woong Park S, Klotzsche M, Wilson DJ, Boshoff HI, Eoh H, Manjunatha U, Blumenthal A, Rhee K, Barry CE 3rd, Aldrich CC, et al. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">PLoS Pathog. 2011 Sep; 7(9):e1002264. Epub 2011 Sep 29.</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/28594172" ref="ordinalpos=1&linkpos=2&log$=relatedarticles&logdbfrom=pubmed">Structure-Based Optimization of Pyridoxal 5'-Phosphate-Dependent Transaminase Enzyme (BioA) Inhibitors that Target Biotin Biosynthesis in Mycobacterium tuberculosis.</a><span class="source">[J Med Chem. 2017]</span><div class="brieflinkpop offscreen_noflow">Structure-Based Optimization of Pyridoxal 5'-Phosphate-Dependent Transaminase Enzyme (BioA) Inhibitors that Target Biotin Biosynthesis in Mycobacterium tuberculosis.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Liu F, Dawadi S, Maize KM, Dai R, Park SW, Schnappinger D, Finzel BC, Aldrich CC. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">J Med Chem. 2017 Jul 13; 60(13):5507-5520. Epub 2017 Jun 22.</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/25556942" ref="ordinalpos=1&linkpos=3&log$=relatedarticles&logdbfrom=pubmed">Target-based identification of whole-cell active inhibitors of biotin biosynthesis in Mycobacterium tuberculosis.</a><span class="source">[Chem Biol. 2015]</span><div class="brieflinkpop offscreen_noflow">Target-based identification of whole-cell active inhibitors of biotin biosynthesis in Mycobacterium tuberculosis.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Park SW, Casalena DE, Wilson DJ, Dai R, Nag PP, Liu F, Boyce JP, Bittker JA, Schreiber SL, Finzel BC, et al. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">Chem Biol. 2015 Jan 22; 22(1):76-86. Epub 2014 Dec 31.</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/17240921" ref="ordinalpos=1&linkpos=4&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> [Development of antituberculous drugs: current status and future prospects].</a><span class="source">[Kekkaku. 2006]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> [Development of antituberculous drugs: current status and future prospects].<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Tomioka H, Namba K. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">Kekkaku. 2006 Dec; 81(12):753-74. </em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/10846444" ref="ordinalpos=1&linkpos=5&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> [Importance of biotin metabolism].</a><span class="source">[Rev Invest Clin. 2000]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> [Importance of biotin metabolism].<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Rodríguez Meléndez R. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">Rev Invest Clin. 2000 Mar-Apr; 52(2):194-9. </em></div></div></li></ul><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed_reviews&uid=25834899" ref="ordinalpos=1&log$=relatedreviews_seeall&logdbfrom=pubmed">See reviews...</a><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=25834899" ref="ordinalpos=1&log$=relatedarticles_seeall&logdbfrom=pubmed">See all...</a></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Recent Activity</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="recent_activity" id="Shutter"></a></div><div class="portlet_content"><div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" id="HTDisplay" class=""><div class="action"><a href="javascript:historyDisplayState('ClearHT')">Clear</a><a href="javascript:historyDisplayState('HTOff')" class="HTOn">Turn Off</a><a href="javascript:historyDisplayState('HTOn')" class="HTOff">Turn On</a></div><ul id="activity"><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=1" href="/portal/utils/pageresolver.fcgi?recordid=67d66b35cde49f3df7d9c8f3">Discovery of small molecule probe that shows anti-tubercular activity via Mtb bi...</a><div class="ralinkpop offscreen_noflow">Discovery of small molecule probe that shows anti-tubercular activity via Mtb bioA (DAPA synthase) enzyme inhibition - Probe Reports from the NIH Molecular Libraries Program<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=2" href="/portal/utils/pageresolver.fcgi?recordid=67d66b342f30673f7bf57597">Small Molecules Targeting the Mitochondrial Permeability Transition - Probe Repo...</a><div class="ralinkpop offscreen_noflow">Small Molecules Targeting the Mitochondrial Permeability Transition - Probe Reports from the NIH Molecular Libraries Program<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=3" href="/portal/utils/pageresolver.fcgi?recordid=67d66b3284f3725e592a94d1">Functional Antagonists of EBI-2 - Probe Reports from the NIH Molecular Libraries...</a><div class="ralinkpop offscreen_noflow">Functional Antagonists of EBI-2 - Probe Reports from the NIH Molecular Libraries Program<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=4" href="/portal/utils/pageresolver.fcgi?recordid=67d66b3267c23b31e0b08753">Allosteric Small Molecule Inhibitors of LMPTP - Probe Reports from the NIH Molec...</a><div class="ralinkpop offscreen_noflow">Allosteric Small Molecule Inhibitors of LMPTP - Probe Reports from the NIH Molecular Libraries Program<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=5" href="/portal/utils/pageresolver.fcgi?recordid=67d66b3167c23b31e0b08473">Progress towards small molecule inhibitors of the Menin-Mixed Lineage Leukemia (...</a><div class="ralinkpop offscreen_noflow">Progress towards small molecule inhibitors of the Menin-Mixed Lineage Leukemia (MLL) interaction with in vivo utility - Probe Reports from the NIH Molecular Libraries Program<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li></ul><p class="HTOn">Your browsing activity is empty.</p><p class="HTOff">Activity recording is turned off.</p><p id="turnOn" class="HTOff"><a href="javascript:historyDisplayState('HTOn')">Turn recording back on</a></p><a class="seemore" href="/sites/myncbi/recentactivity">See more...</a></div></div></div>
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