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 phen...
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Nature Portfolio
2025-02-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-07611-0 |
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| author | Gloria Mavinga Bundutidi Kota Mochizuki Yuichi Matsuo Mizuki Hayashishita Takaya Sakura Yuri Ando Gregory Murray Cook Acharjee Rajib Frédéric Bringaud Michael Boshart Shinjiro Hamano Masakazu Sekijima Kenji Hirayama Kiyoshi Kita Daniel Ken Inaoka |
| author_facet | Gloria Mavinga Bundutidi Kota Mochizuki Yuichi Matsuo Mizuki Hayashishita Takaya Sakura Yuri Ando Gregory Murray Cook Acharjee Rajib Frédéric Bringaud Michael Boshart Shinjiro Hamano Masakazu Sekijima Kenji Hirayama Kiyoshi Kita Daniel Ken Inaoka |
| author_sort | Gloria Mavinga Bundutidi |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-8c3168de62004542845188ac64d264b6 |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-8c3168de62004542845188ac64d264b62025-02-09T12:50:16ZengNature PortfolioCommunications Biology2399-36422025-02-018111110.1038/s42003-025-07611-0Development of tolerance to bedaquiline by overexpression of trypanosomal acetate: succinate CoA transferase in Mycobacterium smegmatisGloria Mavinga Bundutidi0Kota Mochizuki1Yuichi Matsuo2Mizuki Hayashishita3Takaya Sakura4Yuri Ando5Gregory Murray Cook6Acharjee Rajib7Frédéric Bringaud8Michael Boshart9Shinjiro Hamano10Masakazu Sekijima11Kenji Hirayama12Kiyoshi Kita13Daniel Ken Inaoka14Program for Nurturing Global Leaders in Tropical and Emerging Communicable Disease, Graduate School of Biomedical Sciences, Nagasaki UniversityDepartment of Immunogenetics, Institute of Tropical Medicine (NEKKEN), Nagasaki UniversitySchool of Tropical Medicine and Global Health, Nagasaki UniversitySchool of Tropical Medicine and Global Health, Nagasaki UniversityDepartment of Molecular Infection Dynamics, Institute of Tropical Medicine (NEKKEN), Nagasaki UniversityDepartment of Infectious Disease Control, Oita UniversityDepartment of Microbiology and Immunology, University of OtagoDepartment of Molecular Infection Dynamics, Institute of Tropical Medicine (NEKKEN), Nagasaki UniversityLaboratoire de Microbiologie Fondamentale et Pathogénicité (MFP), Université de BordeauxFakultät für Biologie, Genetik, Ludwig-Maximilians-Universität MünchenProgram for Nurturing Global Leaders in Tropical and Emerging Communicable Disease, Graduate School of Biomedical Sciences, Nagasaki UniversityDepartment of Computer Science, Institute of Science TokyoDepartment of Immunogenetics, Institute of Tropical Medicine (NEKKEN), Nagasaki UniversitySchool of Tropical Medicine and Global Health, Nagasaki UniversityDepartment of Molecular Infection Dynamics, Institute of Tropical Medicine (NEKKEN), Nagasaki UniversityAbstract 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.https://doi.org/10.1038/s42003-025-07611-0 |
| spellingShingle | Gloria Mavinga Bundutidi Kota Mochizuki Yuichi Matsuo Mizuki Hayashishita Takaya Sakura Yuri Ando Gregory Murray Cook Acharjee Rajib Frédéric Bringaud Michael Boshart Shinjiro Hamano Masakazu Sekijima Kenji Hirayama Kiyoshi Kita Daniel Ken Inaoka Development of tolerance to bedaquiline by overexpression of trypanosomal acetate: succinate CoA transferase in Mycobacterium smegmatis Communications Biology |
| title | Development of tolerance to bedaquiline by overexpression of trypanosomal acetate: succinate CoA transferase in Mycobacterium smegmatis |
| title_full | Development of tolerance to bedaquiline by overexpression of trypanosomal acetate: succinate CoA transferase in Mycobacterium smegmatis |
| title_fullStr | Development of tolerance to bedaquiline by overexpression of trypanosomal acetate: succinate CoA transferase in Mycobacterium smegmatis |
| title_full_unstemmed | Development of tolerance to bedaquiline by overexpression of trypanosomal acetate: succinate CoA transferase in Mycobacterium smegmatis |
| title_short | Development of tolerance to bedaquiline by overexpression of trypanosomal acetate: succinate CoA transferase in Mycobacterium smegmatis |
| title_sort | development of tolerance to bedaquiline by overexpression of trypanosomal acetate succinate coa transferase in mycobacterium smegmatis |
| url | https://doi.org/10.1038/s42003-025-07611-0 |
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