{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:29:00Z","timestamp":1787016540797,"version":"build-2736575974"},"reference-count":63,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2025,1,31]],"date-time":"2025-01-31T00:00:00Z","timestamp":1738281600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,1,31]],"date-time":"2025-01-31T00:00:00Z","timestamp":1738281600000},"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":[[2025,1,31]]},"abstract":"ABSTRACT<\/jats:title>\n \n \n \n The clinical efficacy of combination drug regimens containing the first-generation diarylquinoline (DARQ) bedaquiline in the treatment of multidrug-resistant tuberculosis has validated ATP synthesis as a vulnerable pathway in\n Mycobacterium tuberculosis<\/jats:italic>\n . New DARQs in clinical development may be even more effective than bedaquiline, including against emerging bedaquiline-resistant strains. Telacebec (T) is a novel cytochrome bc\n 1<\/jats:sub>\n :aa\n 3<\/jats:sub>\n oxidase inhibitor that also inhibits ATP synthesis. Based on its demonstrated efficacy as a monotherapy in mice and in a phase 2a clinical trial, we tested the contribution of T to novel combination therapies against two strains of\n M. tuberculosis<\/jats:italic>\n (H37Rv and HN878) in an established BALB\/c mouse model of tuberculosis in an effort to find more effective regimens. Overall, T was more effective in regimens against the HN878 strain than against the H37Rv strain, a finding supported by the greater vulnerability of the former strain to T and to genetic depletion of QcrB. Against both strains, combinations of a DARQ, clofazimine, and T were highly bactericidal. However, only against HN878 did T contribute synergistically, whereas an antagonistic effect was observed against H37Rv. These results demonstrate the therapeutic potential of T and highlight how differences in the susceptibility of\n M. tuberculosis<\/jats:italic>\n strains could lead to different conclusions about a drug\u2019s potential contribution to novel drug regimens.\n <\/jats:p>\n \n CLINICAL TRIALS<\/jats:title>\n \n This study is registered with\n Clinicaltrials.gov<\/jats:related-object>\n \n as\n \n NCT04890535<\/jats:ext-link>\n \n <\/jats:related-object>\n \n and\n NCT06058299<\/jats:related-object>\n \n \n \n \n \n .\n <\/jats:p>\n <\/jats:sec>\n <\/jats:sec>","DOI":"10.1128\/aac.00962-24","type":"journal-article","created":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T09:09:01Z","timestamp":1733735341000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":7,"title":["Contribution of telacebec to novel drug regimens in a murine tuberculosis model"],"prefix":"10.1128","volume":"69","author":[{"given":"Oliver D.","family":"Komm","sequence":"first","affiliation":[{"name":"Center for TB Research, Johns Hopkins University","place":["Baltimore, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandeep","family":"Tyagi","sequence":"additional","affiliation":[{"name":"Center for TB Research, Johns Hopkins University","place":["Baltimore, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Garcia","sequence":"additional","affiliation":[{"name":"Center for TB Research, Johns Hopkins University","place":["Baltimore, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepak","family":"Almeida","sequence":"additional","affiliation":[{"name":"Center for TB Research, Johns Hopkins University","place":["Baltimore, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Chang","sequence":"additional","affiliation":[{"name":"Center for TB Research, Johns Hopkins University","place":["Baltimore, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si-Yang","family":"Li","sequence":"additional","affiliation":[{"name":"Center for TB Research, Johns Hopkins University","place":["Baltimore, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennie Ruelas","family":"Castillo","sequence":"additional","affiliation":[{"name":"Center for TB Research, Johns Hopkins University","place":["Baltimore, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J.","family":"Converse","sequence":"additional","affiliation":[{"name":"Center for TB Research, Johns Hopkins University","place":["Baltimore, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todd","family":"Black","sequence":"additional","affiliation":[{"name":"TB Alliance","place":["New York, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nader","family":"Fotouhi","sequence":"additional","affiliation":[{"name":"TB Alliance","place":["New York, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1440-9889","authenticated-orcid":true,"given":"Eric L.","family":"Nuermberger","sequence":"additional","affiliation":[{"name":"Center for TB Research, Johns Hopkins University","place":["Baltimore, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2020.589318"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2020.611683"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2021.106509"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.2174\/1874467214666210928152512"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11030-021-10335-y"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.339.6116.130"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2119430"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1901814"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2117166"},{"key":"e_1_3_3_11_2","unstructured":"World Health Organization. 2022. 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