Contribution of telacebec to novel drug regimens in a murine tuberculosis model.

IF 4.1 2区 医学 Q2 MICROBIOLOGY
Oliver D Komm, Sandeep Tyagi, Andrew Garcia, Deepak Almeida, Yong Chang, Si-Yang Li, Jennie Ruelas Castillo, Paul J Converse, Todd Black, Nader Fotouhi, Eric L Nuermberger
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引用次数: 0

Abstract

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 Mycobacterium tuberculosis. New DARQs in clinical development may be even more effective than bedaquiline, including against emerging bedaquiline-resistant strains. Telacebec (T) is a novel cytochrome bc1:aa3 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 M. tuberculosis (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 M. tuberculosis strains could lead to different conclusions about a drug's potential contribution to novel drug regimens.CLINICAL TRIALSThis study is registered with Clinicaltrials.gov as NCT04890535 and NCT06058299.

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来源期刊
CiteScore
10.00
自引率
8.20%
发文量
762
审稿时长
3 months
期刊介绍: Antimicrobial Agents and Chemotherapy (AAC) features interdisciplinary studies that build our understanding of the underlying mechanisms and therapeutic applications of antimicrobial and antiparasitic agents and chemotherapy.
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