{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:05:21Z","timestamp":1791273921807,"version":"4.1.0"},"reference-count":30,"publisher":"American Society for Microbiology","issue":"9","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2015,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Combinations of \u03b2-lactams with clavulanate are currently being investigated for tuberculosis treatment. Since\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Mycobacterium tuberculosis<\/jats:named-content>\n            produces a broad spectrum \u03b2-lactamase, BlaC, the success of this approach could be compromised by the emergence of clavulanate-resistant variants, as observed for inhibitor-resistant TEM variants in enterobacteria. Previous analyses based on site-directed mutagenesis of BlaC have led to the conclusion that this risk was limited. Here, we used a different approach based on determination of the crystal structure of \u03b2-lactamase Bla\n            <jats:sub>MAb<\/jats:sub>\n            of\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Mycobacterium abscessus<\/jats:named-content>\n            , which efficiently hydrolyzes clavulanate. Comparison of Bla\n            <jats:sub>MAb<\/jats:sub>\n            and BlaC allowed for structure-assisted site-directed mutagenesis of BlaC and identification of the G\n            <jats:sup>132<\/jats:sup>\n            N substitution that was sufficient to switch the interaction of BlaC with clavulanate from irreversible inactivation to efficient hydrolysis. The substitution, which restored the canonical SDN motif (SDG\u2192SDN), allowed for efficient hydrolysis of clavulanate, with a more than 10\n            <jats:sup>4<\/jats:sup>\n            -fold increase in\n            <jats:italic>k<\/jats:italic>\n            <jats:sub>cat<\/jats:sub>\n            (0.41 s\n            <jats:sup>\u22121<\/jats:sup>\n            ), without affecting the hydrolysis of other \u03b2-lactams. Mass spectrometry revealed that acylation of BlaC and of its G\n            <jats:sup>132<\/jats:sup>\n            N variant by clavulanate follows similar paths, involving sequential formation of two acylenzymes. Decarboxylation of the first acylenzyme results in a stable secondary acylenzyme in BlaC, whereas hydrolysis occurs in the G\n            <jats:sup>132<\/jats:sup>\n            N variant. The SDN\/SDG polymorphism defines two mycobacterial lineages comprising rapidly and slowly growing species, respectively. Together, these results suggest that the efficacy of \u03b2-lactam\u2013clavulanate combinations may be limited by the emergence of resistance. \u03b2-Lactams active without clavulanate, such as faropenem, should be prioritized for the development of new therapies.\n          <\/jats:p>","DOI":"10.1128\/aac.00598-15","type":"journal-article","created":{"date-parts":[[2015,7,7]],"date-time":"2015-07-07T02:29:57Z","timestamp":1436236197000},"page":"5714-5720","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":35,"title":["Hydrolysis of Clavulanate by Mycobacterium tuberculosis \u03b2-Lactamase BlaC Harboring a Canonical SDN Motif"],"prefix":"10.1128","volume":"59","author":[{"given":"Daria","family":"Soroka","sequence":"first","affiliation":[{"name":"INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, LRMA Equipe 12, Paris, France"},{"name":"Sorbonne Universit\u00e9s, UPMC Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France"},{"name":"Universit\u00e9 Paris Descartes, Sorbonne Paris Cit\u00e9, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France"},{"name":"Open Collaborative Model for Tuberculosis Lead Optimisation (ORCHID) Consortium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In\u00e8s","family":"Li de la Sierra-Gallay","sequence":"additional","affiliation":[{"name":"Fonction et Architecture des Assemblages Macromol\u00e9culaires, Institut de Biologie Int\u00e9grative de la Cellule, Universit\u00e9 Paris-Sud, UMR 9198, Orsay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Dub\u00e9e","sequence":"additional","affiliation":[{"name":"INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, LRMA Equipe 12, Paris, France"},{"name":"Sorbonne Universit\u00e9s, UPMC Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France"},{"name":"Universit\u00e9 Paris Descartes, Sorbonne Paris Cit\u00e9, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France"},{"name":"Open Collaborative Model for Tuberculosis Lead Optimisation (ORCHID) Consortium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9bastien","family":"Triboulet","sequence":"additional","affiliation":[{"name":"INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, LRMA Equipe 12, Paris, France"},{"name":"Sorbonne Universit\u00e9s, UPMC Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France"},{"name":"Universit\u00e9 Paris Descartes, Sorbonne Paris Cit\u00e9, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France"},{"name":"Open Collaborative Model for Tuberculosis Lead Optimisation (ORCHID) Consortium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herman","family":"van Tilbeurgh","sequence":"additional","affiliation":[{"name":"Fonction et Architecture des Assemblages Macromol\u00e9culaires, Institut de Biologie Int\u00e9grative de la Cellule, Universit\u00e9 Paris-Sud, UMR 9198, Orsay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrice","family":"Compain","sequence":"additional","affiliation":[{"name":"INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, LRMA Equipe 12, Paris, France"},{"name":"Sorbonne Universit\u00e9s, UPMC Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France"},{"name":"Universit\u00e9 Paris Descartes, Sorbonne Paris Cit\u00e9, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France"},{"name":"Assistance Publique-H\u00f4pitaux de Paris, H\u00f4pital Europ\u00e9en Georges Pompidou, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lluis","family":"Ballell","sequence":"additional","affiliation":[{"name":"Open Collaborative Model for Tuberculosis Lead Optimisation (ORCHID) Consortium"},{"name":"Diseases of the Developing World (DDW), Tres Cantos Medicines Development Campus (TCMDC), GlaxoSmithKline, Tres Cantos, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Barros","sequence":"additional","affiliation":[{"name":"Open Collaborative Model for Tuberculosis Lead Optimisation (ORCHID) Consortium"},{"name":"Diseases of the Developing World (DDW), Tres Cantos Medicines Development Campus (TCMDC), GlaxoSmithKline, Tres Cantos, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Luc","family":"Mainardi","sequence":"additional","affiliation":[{"name":"INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, LRMA Equipe 12, Paris, France"},{"name":"Sorbonne Universit\u00e9s, UPMC Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France"},{"name":"Universit\u00e9 Paris Descartes, Sorbonne Paris Cit\u00e9, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France"},{"name":"Assistance Publique-H\u00f4pitaux de Paris, H\u00f4pital Europ\u00e9en Georges Pompidou, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Emmanuel","family":"Hugonnet","sequence":"additional","affiliation":[{"name":"INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, LRMA Equipe 12, Paris, France"},{"name":"Sorbonne Universit\u00e9s, UPMC Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France"},{"name":"Universit\u00e9 Paris Descartes, Sorbonne Paris Cit\u00e9, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France"},{"name":"Open Collaborative Model for Tuberculosis Lead Optimisation (ORCHID) Consortium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Arthur","sequence":"additional","affiliation":[{"name":"INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, LRMA Equipe 12, Paris, France"},{"name":"Sorbonne Universit\u00e9s, UPMC Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France"},{"name":"Universit\u00e9 Paris Descartes, Sorbonne Paris Cit\u00e9, 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