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

• DOI: 10.1016/j.jbc.2023.105618
• Publication Date: 2024-01-03T15:19:47Z
• Authors: 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 Grüber
• Keywords: Nontuberculous Mycobacteria

The F1FO-ATP synthase engine is essential for viability and growth of non-tuberculous mycobacteria (NTM) by providing the biological energy ATP keeping homeostasis under hypoxic stress conditions. Here, we report discovery diarylquinoline TBAJ-5307 as a broad spectrum anti-NTM inhibitor, targeting FO-domain preventing rotation proton-translocation. active at low nanomolar concentrations against fast- slow-growing NTM well clinical isolates depleting intrabacterial ATP. As demonstrated fast grower Mycobacterium abscessus, compound potent in vitro vivo, without inducing toxicity. Combining with antibiotics or oral tebipenem-avibactam pair showed attractive potentiation. Furthermore, TBAJ-5307-tebipenem-avibactam cocktail kills pathogen, suggesting novel combination treatment lung infections.