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Title: High efficacy of the F-ATP synthase inhibitor TBAJ-5307 against nontuberculous mycobacteria in vitro and in vivo
Authors: 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
Keywords: Medicine, Health and Life Sciences
Issue Date: 2024
Source: 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-.
Project: NRF-CRP27-2021-0002 
Journal: Journal of Biological Chemistry 
Abstract: 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.
ISSN: 0021-9258
DOI: 10.1016/j.jbc.2023.105618
Schools: School of Biological Sciences 
School of Chemical and Biomedical Engineering 
Lee Kong Chian School of Medicine (LKCMedicine) 
Organisations: Tan Tock Seng Hospital 
Bioinformatics Institute, A*STAR 
National Centre for Infectious Diseases (NCID) 
Research Centres: Singapore Centre for Environmental Life Sciences and Engineering (SCELSE) 
Rights: © 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 (
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SBS Journal Articles

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