Bedaquiline inhibits the yeast and human mitochondrial ATP synthases

• DOI: 10.1038/s42003-020-01173-z
• Publication Date: 2020-08-19T10:03:35Z
• Authors: Min Luo; Wenchang Zhou; Hiral Patel; Anurag P. Srivastava; Jindrich Symersky; Michał M. Bonar; José D. Faraldo-G...; Maofu Liao; David M. Mueller
• Keywords: Bedaquiline

Abstract Bedaquiline (BDQ, Sirturo) has been approved to treat multidrug resistant forms of Mycobacterium tuberculosis . Prior studies suggested that BDQ was a selective inhibitor the ATP synthase from M. However, Sirturo treatment leads an increased risk cardiac arrhythmias and death, raising concern this adverse effect results inhibition at secondary site. Here we show is potent yeast human mitochondrial synthases. Single-particle cryo-EM reveals site partially overlaps with oligomycin. Molecular dynamics simulations indicate binding mode similar previously seen for mycobacterial enzyme, explaining observed lack selectivity. We propose derivatives ought be made increase its specificity toward enzyme thereby reduce side effects patients are treated Sirturo.