BUNDUTIDI, Gloria Mavinga; MOCHIZUKI, Kota; MATSUO, Yuichi; HAYASHISHITA, Mizuki; SAKURA, Takaya; ANDO, Yuri; COOK, Gregory Murray; RAJIB, Acharjee; BRINGAUD, Frédéric; BOSHART, Michael; HAMANO, Shinjiro; SEKIJIMA, Masakazu; HIRAYAMA, Kenji; KITA, Kiyoshi; INAOKA, Daniel Ken

doi:10.1038/s42003-025-07611-0

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Article de revue

Ce document a été publié dans

Communications Biology. 2025-02-06, vol. 8, n° 1, p. 187

Résumé en anglais

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 levels in modulating the growth inhibitory activity of BDQ at low concentrations. These findings shed light on the intricate interplay between BDQ and mycobacterial energy metabolism, while also providing a novel tool for the development of next-generation ATP synthase-specific inhibitors targeting mycobacteria.< Réduire

Mots clés en anglais

Diarylquinolines

Mycobacterium smegmatis

Coenzyme A-Transferases

Adenosine Triphosphate

Trypanosoma brucei brucei

Bacterial Proteins

Antitubercular Agents

URI

https://oskar-bordeaux.fr/handle/20.500.12278/204774

DOI

http://dx.doi.org/10.1038/s42003-025-07611-0

Unités de recherche

MFP (Laboratoire Microbiologie Fondamentale et Pathogénicité) - UMR 5234

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

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Résumé en anglais

Mots clés en anglais

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Unités de recherche