High efficacy of the F-ATP synthase inhibitor TBAJ-5307 against nontuberculous mycobacteria in vitro and in vivo

High efficacy of the F-ATP synthase inhibitor TBAJ-5307 against nontuberculous mycobacteria in vitro and in vivo

Journal of Biological Chemistry

10.1016/j.jbc.2023.105618

https://doi.org/10.1016/j.jbc.2023.105618

Priya Ragunathan, Patcharaporn Sae-Lao, Claire Hamela, Matthéo Alcaraz, Alexander Krah, Wee Han Poh, Carmen Jia Ern Pee, Albert Yick Hou Lim, Scott A. Rice, Kevin Pethe, Peter J. Bond, Thomas Dick, Laurent Kremer, Roderick W. Bates, Gerhard Gruber

mycobacteria, nontuberculosis mycobacterium, antibiotics, bacterial pathogenesis, membrane protein, ATP synthesis

03 January 2024

Ragunathan, P., Sae-Lao, P., Hamela, C., Alcaraz, M., Krah, A., Poh, W. H., Ern Pee, C. J., Hou Lim, A. Y., 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://doi.org/10.1016/j.jbc.2023.105618

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.

Attribution 4.0 International (CC BY 4.0)

This research / project is supported by the National Research Foundation (NRF) Singapore - Competitive Research Programme (CRP)
Grant Reference no. : NRF-CRP27-2021-0002

This research / project is supported by the Fondation pour la Recherche Médicale - NA
Grant Reference no. : EQU202103012588

https://oar.a-star.edu.sg/communities-collections/articles/22231

0021-9258

Bioinformatics Institute