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

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

  • Commun Biol. 2025 Feb 6;8(1):187. doi: 10.1038/s42003-025-07611-0.
Gloria Mavinga Bundutidi 1 2 3 4 5,  Kota Mochizuki 4 6,  Yuichi Matsuo 7 8,  Mizuki Hayashishita 7,  Takaya Sakura 3 7 9,  Yuri Ando 10,  Gregory Murray Cook 11 12,  Acharjee Rajib 3 7 9,  Frédéric Bringaud 13,  Michael Boshart 14,  Shinjiro Hamano 1 2,  Masakazu Sekijima 15,  Kenji Hirayama 4 7,  Kiyoshi Kita 7 9 16,  Daniel Ken Inaoka 17 18 19 20
Affiliations

Affiliations

  • 1 Program for Nurturing Global Leaders in Tropical and Emerging Communicable Disease, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
  • 2 Department of Parasitology, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, Japan.
  • 3 Department of Molecular Infection Dynamics, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, Japan.
  • 4 Department of Immunogenetics, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, Japan.
  • 5 Department of Paediatrics, Kinshasa University Hospital, University of Kinshasa, Kinshasa, Democratic Republic of Congo.
  • 6 Department of Medical Zoology, Kanazawa Medical University, Ishikawa, Japan.
  • 7 School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan.
  • 8 Graduate School of Life Science, Kumamoto University, Kumamoto, Japan.
  • 9 Department of Infection Biochemistry, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, Japan.
  • 10 Department of Infectious Disease Control, Oita University, Oita, Japan.
  • 11 Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.
  • 12 Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
  • 13 Laboratoire de Microbiologie Fondamentale et Pathogénicité (MFP), Université de Bordeaux, Bordeaux, France.
  • 14 Fakultät für Biologie, Genetik, Ludwig-Maximilians-Universität München, München, Germany.
  • 15 Department of Computer Science, Institute of Science Tokyo, Tokyo, Japan.
  • 16 Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • 17 Department of Molecular Infection Dynamics, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, Japan. danielken@nagasaki-u.ac.jp.
  • 18 School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan. danielken@nagasaki-u.ac.jp.
  • 19 Department of Infection Biochemistry, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, Japan. danielken@nagasaki-u.ac.jp.
  • 20 Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. danielken@nagasaki-u.ac.jp.
PMID: 39915674 DOI: 10.1038/s42003-025-07611-0
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 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.

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