A dual-targeting succinate dehydrogenase and FF-ATP synthase inhibitor rapidly sterilizes replicating and non-replicating Mycobacterium tuberculosis.

Cell chemical biology, Volume: 31, Issue: 4
April 18, 2024
Cara Adolph C, Chen-Yi Cheung CY, Matthew B McNeil MB, William J Jowsey WJ, Zoe C Williams ZC, Kiel Hards K, Liam K Harold LK, Ashraf Aboelela A, Richard S Bujaroski RS, Benjamin J Buckley BJ, Joel D A Tyndall JDA, Zhengqiu Li Z, Julian D Langer JD, Laura Preiss L, Thomas Meier T, Adrie J C Steyn AJC, Kyu Y Rhee KY, Michael Berney M, Michael J Kelso MJ, Gregory M Cook GM

Mycobacterial bioenergetics is a validated target space for antitubercular drug development. Here, we identify BB2-50F, a 6-substituted 5-(N,N-hexamethylene)amiloride derivative as a potent, multi-targeting bioenergetic inhibitor of Mycobacterium tuberculosis. We show that BB2-50F rapidly sterilizes both replicating and non-replicating cultures of M. tuberculosis and synergizes with several tuberculosis drugs. Target identification experiments, supported by docking studies, showed that BB2-50F targets the membrane-embedded c-ring of the FF-ATP synthase and the catalytic subunit (substrate-binding site) of succinate dehydrogenase. Biochemical assays and metabolomic profiling showed that BB2-50F inhibits succinate oxidation, decreases the activity of the tricarboxylic acid (TCA) cycle, and results in succinate secretion from M. tuberculosis. Moreover, we show that the lethality of BB2-50F under aerobic conditions involves the accumulation of reactive oxygen species. Overall, this study identifies BB2-50F as an effective inhibitor of M. tuberculosis and highlights that targeting multiple components of the mycobacterial respiratory chain can produce fast-acting antimicrobials.

Courtesy of the U.S. National Library of Medicine