High efficacy of the F-ATP synthase inhibitor TBAJ-5307 against nontuberculous mycobacteria in vitro and in vivo
Priya Ragunathan, Patcharaporn Sae‐Lao, Claire Hamela, Matthéo Alcaraz, Alexander Krah, Wee Han Poh, Carmen J. E. Pee, Albert Yick Hou Lim, Scott A. Rice, Kévin Pethe, Peter J. Bond, Thomas Dick, Laurent Kremer, Roderick W. Bates, Gerhard Grüber
Abstract
The F 1 F O -ATP synthase engine is essential for viability and growth of non-tuberculous 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 F O -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.