Komm Oliver D, Tyagi Sandeep, Garcia Andrew, Almeida Deepak, Chang Yong, Li Si-Yang, Castillo Jennie Ruelas, Converse Paul J, Black Todd, Fotouhi Nader, Nuermberger Eric L
Center for TB Research, Johns Hopkins University, Baltimore, Maryland, USA.
TB Alliance, New York, New York, USA.
Antimicrob Agents Chemother. 2025 Jan 31;69(1):e0096224. doi: 10.1128/aac.00962-24. Epub 2024 Dec 9.
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 . 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:aa 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 (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 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.
含第一代二芳基喹啉（DARQ）类药物贝达喹啉的联合用药方案在治疗耐多药结核病方面的临床疗效已证实ATP合成是结核分枝杆菌中的一个易损途径。正在临床开发的新型DARQ类药物可能比贝达喹啉更有效，包括对新出现的贝达喹啉耐药菌株。替拉塞贝（T）是一种新型细胞色素bc1-aa3氧化酶抑制剂，也能抑制ATP合成。基于其在小鼠单药治疗及2a期临床试验中所显示的疗效，我们在已建立的BALB/c小鼠结核病模型中测试了T对针对两株结核分枝杆菌（H37Rv和HN878）的新型联合疗法的作用，以寻找更有效的治疗方案。总体而言，T在针对HN878菌株的治疗方案中比针对H37Rv菌株更有效，这一发现得到了前一种菌株对T及QcrB基因缺失更敏感的支持。针对这两种菌株，DARQ、氯法齐明和T的联合用药具有高度杀菌作用。然而，只有针对HN878时T才具有协同作用，而针对H37Rv则观察到拮抗作用。这些结果证明了T的治疗潜力，并突出了结核分枝杆菌菌株易感性的差异如何可能导致关于一种药物对新型药物方案潜在贡献的不同结论。临床试验本研究已在Clinicaltrials.gov上注册，注册号为NCT04890535和NCT06058299。
