Development of tolerance to bedaquiline by overexpression of trypanosomal acetate: succinate CoA transferase in Mycobacterium smegmatis.

ABSTRACT: The F-type ATP synthase inhibitor bedaquiline (BDQ) is a potent inhibitor of mycobacterial growth and this inhibition cannot be rescued by fermentable carbon sources that would supply ATP by an alternative pathway (substrate level phosphorylation). To gain mechanistic insight into this phenomenon, we employed a metabolic engineering approach. We introduced into Mycobacterium smegmatis an alternative ATP production pathway by substrate-level phosphorylation, specifically through overexpression of trypanosomal acetate:succinate co-enzyme A (CoA) transferase (ASCT). Intriguingly, the overexpression of ASCT partially restored intracellular ATP levels and resulted in acquired tolerance to BDQ growth inhibition at low, but not high concentrations of BDQ. These results implicate intracellular ATP

SUBMITTER: Bundutidi GM 

PROVIDER: S-EPMC11802737 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature