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

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

doi:10.1016/j.chembiol.2023.12.002

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

Cell Chem Biol. 2024 Apr 18;31(4):683-698.e7. doi: 10.1016/j.chembiol.2023.12.002. Epub 2023 Dec 26.

Authors

Cara Adolph¹, Chen-Yi Cheung², Matthew B McNeil¹, William J Jowsey¹, Zoe C Williams², Kiel Hards², Liam K Harold², Ashraf Aboelela³, Richard S Bujaroski³, Benjamin J Buckley³, Joel D A Tyndall⁴, Zhengqiu Li⁵, Julian D Langer⁶, Laura Preiss⁷, Thomas Meier⁸, Adrie J C Steyn⁹, Kyu Y Rhee¹⁰, Michael Berney¹¹, Michael J Kelso³, Gregory M Cook¹²

Affiliations

¹ Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Private Bag 92019, Auckland 1042, New Zealand.
² Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand.
³ Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia; Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia.
⁴ School of Pharmacy, University of Otago, Dunedin 9054, New Zealand.
⁵ School of Pharmacy, Jinan University, Guangzhou, China.
⁶ Proteomics, Max Planck Institute of Biophysics, Max-von-Laue-Strasse 3, 60438 Frankfurt am Main, Germany.
⁷ Structural Biology, Max Planck Institute of Biophysics, Max-von-Laue-Strasse 3, 60438 Frankfurt am Main, Germany.
⁸ Department of Life Sciences, Imperial College London, Exhibition Road, London SW7 2AZ, UK; Private University in the Principality of Liechtenstein, Triesen, Liechtenstein.
⁹ Africa Health Research Institute, University of KwaZulu Natal, Durban, KwaZulu, Natal, South Africa; Department of Microbiology, Centers for AIDs Research and Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA.
¹⁰ Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, Ithaca, NY 14853, USA; Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, Cornell University, Ithaca, NY 14853, USA.
¹¹ Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, NY, USA.
¹² Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Private Bag 92019, Auckland 1042, New Zealand. Electronic address: greg.cook@otago.ac.nz.

PMID: 38151019
DOI: 10.1016/j.chembiol.2023.12.002

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.

Keywords: F(1)F(o)-ATP synthase; Mycobacterium tuberculosis; SDH; amiloride; bioenergetics; inhibitors; metabolism; succinate dehydrogenase,.

MeSH terms

Adenosine Triphosphate
Antitubercular Agents / chemistry
Enzyme Inhibitors / pharmacology
Humans
Mycobacterium tuberculosis*
Succinate Dehydrogenase / metabolism
Succinate Dehydrogenase / pharmacology
Succinates
Tuberculosis* / drug therapy

Substances

Succinate Dehydrogenase
Antitubercular Agents
Adenosine Triphosphate
Enzyme Inhibitors
Succinates