High efficacy of the F-ATP synthase inhibitor TBAJ-5307 against nontuberculous mycobacteria in vitro and in vivo
The F1FO-ATP synthase engine is essential for viability and growth of nontuberculous mycobacteria (NTM) by providing the biological energy ATP and keeping ATP homeostasis under hypoxic stress conditions. Here, we report the discovery of the diarylquinoline TBAJ-5307 as a broad spectrum anti-NTM...
| Main Authors: | , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2024
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/175508 |
| _version_ | 1811678958313275392 |
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| author | Ragunathan, Priya Sae-Lao, Patcharaporn Hamela, Claire Alcaraz, Matthéo Krah, Alexander Poh, Wee Han Pee, Carmen Jia Ern Lim, Albert Yick Hou Rice, Scott A. Pethe, Kevin Bond, Peter J. Dick, Thomas Kremer, Laurent Bates, Roderick Wayland Grüber, Gerhard |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Ragunathan, Priya Sae-Lao, Patcharaporn Hamela, Claire Alcaraz, Matthéo Krah, Alexander Poh, Wee Han Pee, Carmen Jia Ern Lim, Albert Yick Hou Rice, Scott A. Pethe, Kevin Bond, Peter J. Dick, Thomas Kremer, Laurent Bates, Roderick Wayland Grüber, Gerhard |
| author_sort | Ragunathan, Priya |
| collection | NTU |
| description | The F1FO-ATP synthase engine is essential for viability and
growth of nontuberculous mycobacteria (NTM) by providing
the biological energy ATP and keeping ATP homeostasis under
hypoxic stress conditions. Here, we report the discovery of the
diarylquinoline TBAJ-5307 as a broad spectrum anti-NTM
inhibitor, targeting the FO domain of the engine and preventing rotation and proton translocation. TBAJ-5307 is active at
low nanomolar concentrations against fast- and slow-growing
NTM as well as clinical isolates by depleting intrabacterial
ATP. As demonstrated for the fast grower Mycobacterium
abscessus, the compound is potent in vitro and in vivo, without
inducing toxicity. Combining TBAJ-5307 with anti-NTM antibiotics or the oral tebipenem–avibactam pair showed attractive potentiation. Furthermore, the TBAJ-5307–tebipenem–
avibactam cocktail kills the pathogen, suggesting a novel oral
combination for the treatment of NTM lung infections. |
| first_indexed | 2024-10-01T03:01:32Z |
| format | Journal Article |
| id | ntu-10356/175508 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T03:01:32Z |
| publishDate | 2024 |
| record_format | dspace |
| spelling | ntu-10356/1755082024-04-29T15:32:57Z High efficacy of the F-ATP synthase inhibitor TBAJ-5307 against nontuberculous mycobacteria in vitro and in vivo Ragunathan, Priya Sae-Lao, Patcharaporn Hamela, Claire Alcaraz, Matthéo Krah, Alexander Poh, Wee Han Pee, Carmen Jia Ern Lim, Albert Yick Hou Rice, Scott A. Pethe, Kevin Bond, Peter J. Dick, Thomas Kremer, Laurent Bates, Roderick Wayland Grüber, Gerhard School of Biological Sciences School of Chemical and Biomedical Engineering Lee Kong Chian School of Medicine (LKCMedicine) Tan Tock Seng Hospital Bioinformatics Institute, A*STAR National Centre for Infectious Diseases (NCID) Singapore Centre for Environmental Life Sciences and Engineering (SCELSE) Medicine, Health and Life Sciences Mycobacteria Nontuberculosis mycobacterium The F1FO-ATP synthase engine is essential for viability and growth of nontuberculous mycobacteria (NTM) by providing the biological energy ATP and keeping ATP homeostasis under hypoxic stress conditions. Here, we report the discovery of the diarylquinoline TBAJ-5307 as a broad spectrum anti-NTM inhibitor, targeting the FO domain of the engine and preventing rotation and proton translocation. TBAJ-5307 is active at low nanomolar concentrations against fast- and slow-growing NTM as well as clinical isolates by depleting intrabacterial ATP. As demonstrated for the fast grower Mycobacterium abscessus, the compound is potent in vitro and in vivo, without inducing toxicity. Combining TBAJ-5307 with anti-NTM antibiotics or the oral tebipenem–avibactam pair showed attractive potentiation. Furthermore, the TBAJ-5307–tebipenem– avibactam cocktail kills the pathogen, suggesting a novel oral combination for the treatment of NTM lung infections. National Research Foundation (NRF) Published version This research was supported by the National Research Foundation (NRF) Singapore, NRF Competitive Research Programme (CRP), grant award number NRF-CRP27-2021-0002,and the Fondation pour la Recherche Médicale (Equipe FRM; grant no.: EQU202103012588). We acknowledge the Ministère de l’Enseignement Supérieur, de la Recherche et de l’Innovation for funding the PhD of MA. The computational work for this article was performed on resources of the National Supercomputing Centre, Singapore (https://www.nscc.sg). We acknowledge support from BII core funds. 2024-04-26T01:34:44Z 2024-04-26T01:34:44Z 2024 Journal Article Ragunathan, P., Sae-Lao, P., Hamela, C., Alcaraz, M., Krah, A., Poh, W. H., Pee, C. J. E., Lim, A. Y. H., Rice, S. A., Pethe, K., Bond, P. J., Dick, T., Kremer, L., Bates, R. W. & Grüber, G. (2024). High efficacy of the F-ATP synthase inhibitor TBAJ-5307 against nontuberculous mycobacteria in vitro and in vivo. Journal of Biological Chemistry, 300(2), 105618-. https://dx.doi.org/10.1016/j.jbc.2023.105618 0021-9258 https://hdl.handle.net/10356/175508 10.1016/j.jbc.2023.105618 2 300 105618 en NRF-CRP27-2021-0002 Journal of Biological Chemistry © 2024 The Author. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). application/pdf application/pdf |
| spellingShingle | Medicine, Health and Life Sciences Mycobacteria Nontuberculosis mycobacterium Ragunathan, Priya Sae-Lao, Patcharaporn Hamela, Claire Alcaraz, Matthéo Krah, Alexander Poh, Wee Han Pee, Carmen Jia Ern Lim, Albert Yick Hou Rice, Scott A. Pethe, Kevin Bond, Peter J. Dick, Thomas Kremer, Laurent Bates, Roderick Wayland Grüber, Gerhard High efficacy of the F-ATP synthase inhibitor TBAJ-5307 against nontuberculous mycobacteria in vitro and in vivo |
| title | High efficacy of the F-ATP synthase inhibitor TBAJ-5307 against nontuberculous mycobacteria in vitro and in vivo |
| title_full | High efficacy of the F-ATP synthase inhibitor TBAJ-5307 against nontuberculous mycobacteria in vitro and in vivo |
| title_fullStr | High efficacy of the F-ATP synthase inhibitor TBAJ-5307 against nontuberculous mycobacteria in vitro and in vivo |
| title_full_unstemmed | High efficacy of the F-ATP synthase inhibitor TBAJ-5307 against nontuberculous mycobacteria in vitro and in vivo |
| title_short | High efficacy of the F-ATP synthase inhibitor TBAJ-5307 against nontuberculous mycobacteria in vitro and in vivo |
| title_sort | high efficacy of the f atp synthase inhibitor tbaj 5307 against nontuberculous mycobacteria in vitro and in vivo |
| topic | Medicine, Health and Life Sciences Mycobacteria Nontuberculosis mycobacterium |
| url | https://hdl.handle.net/10356/175508 |
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