{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T22:18:01Z","timestamp":1768515481716,"version":"3.49.0"},"posted":{"date-parts":[[2024,10,10]]},"group-title":"Microbiology","reference-count":47,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,10,10]],"date-time":"2024-10-10T00:00:00Z","timestamp":1728518400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,10,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Tuberculosis (TB) is historically the world\u2019s deadliest infectious disease. New TB drugs that can avoid pre-existing resistance are desperately needed. The \u03b2-lactams are the oldest and most widely used class of antibiotics to treat bacterial infections but, for a variety of reasons, they were largely ignored until recently as a potential treatment option for TB. Recently, a growing body of evidence indicates that later-generation carbapenems in the presence of \u03b2-lactamase inhibitors could play a role in TB treatment. However, most of these drugs can only be administered intravenously in the clinic.<\/jats:p>\n                <jats:p>\n                  We performed a screening of \u03b2-lactams against intracellular\n                  <jats:italic>Mycobacterium tuberculosis (Mtb)<\/jats:italic>\n                  and identified sanfetrinem cilexetil as a promising oral \u03b2-lactam candidate. Preclinical\n                  <jats:italic>in vitro<\/jats:italic>\n                  and\n                  <jats:italic>in vivo<\/jats:italic>\n                  studies demonstrated that: (i) media composition impacts the activity of sanfetrinem against\n                  <jats:italic>Mtb<\/jats:italic>\n                  , being more potent in the presence of physiologically relevant cholesterol as the only carbon source, compared to the standard broth media; (ii) sanfetrinem shows broad spectrum activity against\n                  <jats:italic>Mtb<\/jats:italic>\n                  clinical isolates, including MDR\/XDR strains; (iii) sanfetrinem is rapidly bactericidal\n                  <jats:italic>in vitro<\/jats:italic>\n                  against\n                  <jats:italic>Mtb<\/jats:italic>\n                  despite being poorly stable in the assay media; (iv) there are strong\n                  <jats:italic>in vitro<\/jats:italic>\n                  synergistic interactions with amoxicillin, ethambutol, rifampicin and rifapentine and, (v) sanfetrinem cilexetil is active in an\n                  <jats:italic>in vivo<\/jats:italic>\n                  model of infection. These data, together with robust pre-clinical and clinical studies of broad-spectrum carbapenem antibiotics carried out in the 1990s by GSK, identified sanfetrinem as having potential for treating TB and catalyzed a repurposing proof-of-concept Phase 2a clinical study (\n                  <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT05388448\">NCT05388448<\/jats:ext-link>\n                  ) currently underway in South Africa.\n                <\/jats:p>","DOI":"10.1101\/2024.10.10.617558","type":"posted-content","created":{"date-parts":[[2024,10,10]],"date-time":"2024-10-10T23:35:12Z","timestamp":1728603312000},"source":"Crossref","is-referenced-by-count":1,"title":["Sanfetrinem, an oral \u03b2-lactam antibiotic repurposed for the treatment of tuberculosis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8480-0325","authenticated-orcid":false,"given":"Santiago","family":"Ram\u00f3n-Garc\u00eda","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rub\u00e9n","family":"Gonz\u00e1lez del R\u00edo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda Pilar","family":"Arenaz-Callao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helena","family":"Boshoff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joaqu\u00edn","family":"Rull\u00e1s","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Anca","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M\u00f3nica Cacho","family":"Izquierdo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Esther","family":"Porras de Francisco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Esther P\u00e9rez","family":"Herr\u00e1n","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angel","family":"Santos-Villarejo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alfonso","family":"Mendoza-Losana","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Santiago","family":"Ferrer-Bazaga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles J.","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David Barros","family":"Aguirre","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert H.","family":"Bates","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024101209450744000_2024.10.10.617558v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/S2666-5247(22)00359-7"},{"key":"2024101209450744000_2024.10.10.617558v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(21)00470-9"},{"issue":"3","key":"2024101209450744000_2024.10.10.617558v1.3","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1021\/acsinfecdis.1c00570","article-title":"Identification of \u03b2-lactams active against Mycobacterium tuberculosis by a consortium of pharmaceutical companies and academic institutions","volume":"8","year":"2022","journal-title":"ACS Infectious Diseases"},{"key":"2024101209450744000_2024.10.10.617558v1.4","doi-asserted-by":"publisher","DOI":"10.1002\/path.1700580320"},{"issue":"2","key":"2024101209450744000_2024.10.10.617558v1.5","first-page":"95","article-title":"Penicillin: The Robert Campbell Oration","volume":"13","year":"1944","journal-title":"The Ulster medical journal"},{"key":"2024101209450744000_2024.10.10.617558v1.6","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.41.5.1182"},{"issue":"10","key":"2024101209450744000_2024.10.10.617558v1.7","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1021\/acsinfecdis.8b00160","article-title":"Pharmacokinetics of \u03b2-lactam antibiotics: clues from the past to help discover long-acting oral drugs in the future","volume":"4","year":"2018","journal-title":"ACS infectious diseases"},{"key":"2024101209450744000_2024.10.10.617558v1.8","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1379.004"},{"key":"2024101209450744000_2024.10.10.617558v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2120"},{"issue":"3","key":"2024101209450744000_2024.10.10.617558v1.10","doi-asserted-by":"crossref","first-page":"373","DOI":"10.3390\/ijms17030373","article-title":"Carbapenems to treat multidrug and extensively drug-resistant tuberculosis: a systematic review","volume":"17","year":"2016","journal-title":"International journal of molecular sciences"},{"issue":"11","key":"2024101209450744000_2024.10.10.617558v1.11","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.5588\/ijtld.16.0498","article-title":"Carbapenems against Mycobacterium tuberculosis: a review of the evidence","volume":"20","year":"2016","journal-title":"The International Journal of Tuberculosis and Lung Disease"},{"key":"2024101209450744000_2024.10.10.617558v1.12","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1513236"},{"issue":"4","key":"2024101209450744000_2024.10.10.617558v1.13","doi-asserted-by":"crossref","first-page":"558","DOI":"10.5588\/ijtld.11.0414","article-title":"Clinical use of the meropenem-clavulanate combination for extensively drug-resistant tuberculosis [Case study]","volume":"16","year":"2012","journal-title":"The International journal of tuberculosis and lung disease"},{"issue":"22","key":"2024101209450744000_2024.10.10.617558v1.14","doi-asserted-by":"crossref","first-page":"2791","DOI":"10.1016\/S0960-894X(96)00515-X","article-title":"Synthesis and antibacterial, activity of 4-ureido trinems","volume":"6","year":"1996","journal-title":"Bioorganic & Medicinal Chemistry Letters"},{"key":"2024101209450744000_2024.10.10.617558v1.15","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.40.5.1248"},{"issue":"14","key":"2024101209450744000_2024.10.10.617558v1.16","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1016\/0960-894X(96)00292-2","article-title":"Synthesis and antimicrobial activity of 4-amino trinems","volume":"6","year":"1996","journal-title":"Bioorganic & Medicinal Chemistry Letters"},{"key":"2024101209450744000_2024.10.10.617558v1.17","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01920-15"},{"key":"2024101209450744000_2024.10.10.617558v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.tube.2010.12.007"},{"issue":"1","key":"2024101209450744000_2024.10.10.617558v1.19","doi-asserted-by":"crossref","first-page":"34293","DOI":"10.1038\/srep34293","article-title":"Repurposing clinically approved cephalosporins for tuberculosis therapy","volume":"6","year":"2016","journal-title":"Scientific reports"},{"issue":"5","key":"2024101209450744000_2024.10.10.617558v1.20","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1080\/21505594.2015.1044195","article-title":"The mycobacterial P55 efflux pump is required for optimal growth on cholesterol","volume":"6","year":"2015","journal-title":"Virulence"},{"key":"2024101209450744000_2024.10.10.617558v1.21","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00474-11"},{"issue":"4","key":"2024101209450744000_2024.10.10.617558v1.22","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.ijmyco.2014.09.002","article-title":"Resazurin microtiter assay for isoniazid, rifampicin, ethambutol and streptomycin resistance detection in Mycobacterium tuberculosis: updated meta-analysis","volume":"3","year":"2014","journal-title":"International journal of mycobacteriology"},{"key":"2024101209450744000_2024.10.10.617558v1.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2014.11.016"},{"key":"2024101209450744000_2024.10.10.617558v1.24","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01063-15"},{"key":"2024101209450744000_2024.10.10.617558v1.25","doi-asserted-by":"crossref","first-page":"677005","DOI":"10.3389\/fphar.2021.677005","article-title":"Cefdinir and \u03b2-lactamase inhibitor independent efficacy against mycobacterium tuberculosis","volume":"12","year":"2021","journal-title":"Frontiers in Pharmacology"},{"key":"2024101209450744000_2024.10.10.617558v1.26","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0605728104"},{"key":"2024101209450744000_2024.10.10.617558v1.27","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/45.2.159"},{"key":"2024101209450744000_2024.10.10.617558v1.28","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01824-10"},{"key":"2024101209450744000_2024.10.10.617558v1.29","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.05690-11"},{"key":"2024101209450744000_2024.10.10.617558v1.30","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00023-13"},{"key":"2024101209450744000_2024.10.10.617558v1.31","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201701-0218PP"},{"issue":"10","key":"2024101209450744000_2024.10.10.617558v1.32","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1164\/rccm.202108-1976OC","article-title":"Early bactericidal activity of meropenem plus clavulanate (with or without rifampin) for tuberculosis: the COMRADE randomized, phase 2A clinical trial","volume":"205","year":"2022","journal-title":"American journal of respiratory and critical care medicine"},{"issue":"14","key":"2024101209450744000_2024.10.10.617558v1.33","doi-asserted-by":"crossref","first-page":"1857","DOI":"10.1016\/S0960-894X(97)00326-0","article-title":"Tricyclic \u03b2-lactams: Total synthesis and antibacterial activity of 5\u03b1-methoxyethyl and 5\u03b1-hydroxyethyl trinems","volume":"7","year":"1997","journal-title":"Bioorganic & Medicinal Chemistry Letters"},{"issue":"19","key":"2024101209450744000_2024.10.10.617558v1.34","doi-asserted-by":"crossref","first-page":"9780","DOI":"10.1021\/jp044192m","article-title":"Molecular modeling and chemical reactivity of sanfetrinem and derivatives","volume":"109","year":"2005","journal-title":"The Journal of Physical Chemistry B"},{"key":"2024101209450744000_2024.10.10.617558v1.35","unstructured":"Prezelj, A. , U. Urleb , and G. Vilfan , Use of inhibitor of beta-lactamases and its combination with beta-lactam antibiotics. 2011, Google Patents."},{"key":"2024101209450744000_2024.10.10.617558v1.36","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.40.9.2142"},{"key":"2024101209450744000_2024.10.10.617558v1.37","doi-asserted-by":"publisher","DOI":"10.1586\/eri.12.96"},{"key":"2024101209450744000_2024.10.10.617558v1.38","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/42.2.249"},{"key":"2024101209450744000_2024.10.10.617558v1.39","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02924-15"},{"key":"2024101209450744000_2024.10.10.617558v1.40","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.41.10.2173"},{"key":"2024101209450744000_2024.10.10.617558v1.41","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.03461-14"},{"issue":"1","key":"2024101209450744000_2024.10.10.617558v1.42","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/ncomms1060","article-title":"A chemical genetic screen in Mycobacterium tuberculosis identifies carbon-source-dependent growth inhibitors devoid of in vivo efficacy","volume":"1","year":"2010","journal-title":"Nature communications"},{"key":"2024101209450744000_2024.10.10.617558v1.43","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.ebiom.2016.05.041","article-title":"Paradoxical Hypersusceptibility of Drug-resistant Mycobacteriumtuberculosis to \u03b2-lactam Antibiotics","volume":"9","year":"2016","journal-title":"EBioMedicine"},{"key":"2024101209450744000_2024.10.10.617558v1.44","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dks395"},{"key":"2024101209450744000_2024.10.10.617558v1.45","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01158-15"},{"issue":"6","key":"2024101209450744000_2024.10.10.617558v1.46","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1016\/j.jmii.2015.08.025","article-title":"Anti-Mycobacterium tuberculosis activity of antituberculosis drugs and amoxicillin\/clavulanate combination","volume":"49","year":"2016","journal-title":"Journal of microbiology, immunology and infection"},{"issue":"1","key":"2024101209450744000_2024.10.10.617558v1.47","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1186\/s13063-022-06473-9","article-title":"Comparison of 8 weeks standard treatment (rifampicin plus clarithromycin) vs. 4 weeks standard plus amoxicillin\/clavulanate treatment [RC8 vs. RCA4] to shorten Buruli ulcer disease therapy (the BLMs4BU trial): study protocol for a randomized controlled multi-centre trial in Benin","volume":"23","year":"2022","journal-title":"Trials"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.10.10.617558","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T07:13:54Z","timestamp":1768461234000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2024.10.10.617558"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,10]]},"references-count":47,"URL":"https:\/\/doi.org\/10.1101\/2024.10.10.617558","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1016\/j.drup.2025.101213","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2024,10,10]]},"subtype":"preprint"}}