2. Academic Validation
  3. A dual-targeting succinate dehydrogenase and F1Fo-ATP synthase inhibitor rapidly sterilizes replicating and non-replicating Mycobacterium tuberculosis

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

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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