Li Dongshuo, Li Liang, Zhang Ye, Cheng Kai, Liang Wenwen, Nuermberger Eric, Qi Xianglong, Fu Lei, Wang Bin, Yan Chenxia, Xu Rui, Lu Yu, Xu Jian
Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China.
Department of Medicine, Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Antimicrob Agents Chemother. 2025 Jun 4;69(6):e0001925. doi: 10.1128/aac.00019-25. Epub 2025 Apr 22.
in both replicating and non-replicating states relies on oxidative phosphorylation (OxPhos) to generate ATP for its growth and survival. Our research delved into the efficacy of novel regimens targeting the OxPhos pathway in murine models. The combination of bedaquiline, clofazimine, pyrazinamide, alongside telacebec, and SQ109 was investigated against both wild-type H37Rv and an mutant with cross-resistance between bedaquiline and clofazimine. The results demonstrated that the combination regimens, particularly bedaquiline + clofazimine + pyrazinamide (BCZ) along with telacebec (BCZT) and SQ109 (BCZS), exhibit significantly enhanced bactericidal activity compared to bedaquiline alone and sterilizing potential against . Notably, the BCZT regimen showed superior activity compared to other treatment regimens in mutant-infected BALB/c mice. The addition of T to BCZ prevented the amplification of bedaquiline-resistant mutants and reduced the number of mice relapsing. Our finding underscores the potential of targeting the OxPhos pathway to combat , paving the way for innovative approaches in tuberculosis therapy.
在复制和非复制状态下，（结核菌）都依赖氧化磷酸化（OxPhos）来产生ATP以实现其生长和存活。我们的研究深入探讨了针对OxPhos途径的新型治疗方案在小鼠模型中的疗效。研究了贝达喹啉、氯法齐明、吡嗪酰胺与替拉塞贝以及SQ109联合使用对野生型H37Rv和对贝达喹啉与氯法齐明具有交叉耐药性的突变体的效果。结果表明，联合治疗方案，特别是贝达喹啉+氯法齐明+吡嗪酰胺（BCZ）与替拉塞贝（BCZT）和SQ109（BCZS）联合使用，与单独使用贝达喹啉相比，具有显著增强的杀菌活性以及对……的灭菌潜力。值得注意的是，在感染突变体的BALB/c小鼠中，BCZT方案显示出比其他治疗方案更优越的活性。在BCZ中添加T可防止贝达喹啉耐药突变体的扩增并减少复发小鼠的数量。我们的发现强调了靶向OxPhos途径对抗……的潜力，为结核病治疗的创新方法铺平了道路。
