A dual-targeting succinate dehydrogenase and F1Fo-ATP synthase inhibitor 
rapidly sterilizes replicating and non-replicating Mycobacterium tuberculosis

Adolph, Cara; Cheung, Chen-Yi; McNeil, Matthew B.; Jowsey, William J.; Williams, Zoe C.; Hards, Kiel; Harold, Liam K.; Aboelela, Ashraf; Bujaroski, Richard S.; Buckley, Benjamin J.; Tyndall, Joel D. A.; Li, Zhengqiu; Langer, Julian D.; Preiss, Laura; Meier, Thomas; Steyn, Adrie J. C.; Rhee, Kyu Y.; Berney, Michael; Kelso, Michael J.; Cook, Gregory M.

doi:10.1016/j.chembiol.2023.12.002

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A dual-targeting succinate dehydrogenase and F₁F_o-ATP synthase inhibitor rapidly sterilizes replicating and non-replicating Mycobacterium tuberculosis

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Langer, Julian D.
Proteomics and Mass Spectrometry, Max Planck Institute of Biophysics, Max Planck Society;

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Preiss, Laura
Department of Structural Biology, Max Planck Institute of Biophysics, Max Planck Society;

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Citation

Adolph, C., Cheung, C.-Y., McNeil, M. B., Jowsey, W. J., Williams, Z. C., Hards, K., et al. (2024). A dual-targeting succinate dehydrogenase and F₁F_o-ATP synthase inhibitor rapidly sterilizes replicating and non-replicating Mycobacterium tuberculosis. Cell Chemical Biology, 31, 683-698.e7. doi:10.1016/j.chembiol.2023.12.002.

Cite as: https://hdl.handle.net/21.11116/0000-000E-394D-D

Abstract

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 F₁F_o-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.