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

  • Cell Chem Biol. 2023 Dec 21:S2451-9456(23)00432-4. doi: 10.1016/j.chembiol.2023.12.002.
Cara Adolph  1 ,  Chen-Yi Cheung  2 ,  Matthew B McNeil  1 ,  William J Jowsey  1 ,  Zoe C Williams  2 ,  Kiel Hards  2 ,  Liam K Harold  2 ,  Ashraf Aboelela  3 ,  Richard S Bujaroski  3 ,  Benjamin J Buckley  3 ,  Joel D A Tyndall  4 ,  Zhengqiu Li  5 ,  Julian D Langer  6 ,  Laura Preiss  7 ,  Thomas Meier  8 ,  Adrie J C Steyn  9 ,  Kyu Y Rhee  10 ,  Michael Berney  11 ,  Michael J Kelso  3 ,  Gregory M Cook  12
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: [email protected].
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 F1Fo-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,.
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