Efficacy of novel regimens targeting oxidative phosphorylation in <i>Mycobacterium tuberculosis</i>

<i>Mycobacterium tuberculosis</i> 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 <i>M. tuberculosis</i> H37Rv and an <i>Rv0678</i> 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 <i>M. tuberculosis in vivo</i>. Notably, the BCZT regimen showed superior activity compared to other treatment regimens in <i>Rv0678</i> 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 <i>M. tuberculosis</i>, paving the way for innovative approaches in tuberculosis therapy.