Development of tolerance to bedaquiline by overexpression of trypanosomal acetate: succinate CoA transferase in Mycobacterium smegmatis
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.
Authors
- Michael Boshart (ORCID: https://orcid.org/0000-0002-5070-2663)
- Masakazu Sekijima (ORCID: https://orcid.org/0000-0002-3806-9535)
- Mizuki Hayashishita
- Yuichi Matsuo (ORCID: https://orcid.org/0000-0001-6942-3202)
- Gloria Mavinga Bundutidi
- Shinjiro Hamano (ORCID: https://orcid.org/0000-0003-3881-8337)
- Yusuke Ando (ORCID: https://orcid.org/0000-0002-8208-4871)
- Gregory Murray Cook (ORCID: https://orcid.org/0000-0001-8349-1500)
- D.K. Inaoka (ORCID: https://orcid.org/0000-0002-9791-927X)
- Takaya Sakura (ORCID: https://orcid.org/0000-0002-8320-8485)
- Kenji Hirayama
- Kiyoshi Kita (ORCID: https://orcid.org/0000-0002-0426-4308)
- Frédéric Bringaud (ORCID: https://orcid.org/0000-0003-4552-6877)
- Kota Mochizuki (ORCID: https://orcid.org/0000-0002-2335-1503)
- Acharjee Rajib
Institutions
- Université de Bordeaux (FR)
- University of Auckland (NZ)
- Kanazawa Medical University (JP)
- Oita University (JP)
- Kinshasa General Hospital (CD)
- University of Kinshasa (CD)
- Maurice Wilkins Centre (NZ)
- Institut Polytechnique de Bordeaux (FR)
- Nagasaki University (JP)
- Laboratoire de Microbiologie Fondamentale et Pathogénicité (FR)
- Institute of Science Tokyo (JP)
- The University of Tokyo (JP)
- University of Otago (NZ)
- Ludwig-Maximilians-Universität München (DE)
- Kumamoto University (JP)
Publication Details
- Journal
- Communications Biology
- Published
- 2025-02-06
- DOI
- https://doi.org/10.1038/s42003-025-07611-0
- Citations
- 2
- Primary Topic
- Tuberculosis Research and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 2.79
Funders
- Japan Agency for Medical Research and Development
- Ministry of Education, Culture, Sports, Science and Technology
- Japan Society for the Promotion of Science
- Science and Technology Research Partnership for Sustainable Development