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

doi:10.1016/j.chembiol.2023.12.002

. 2024 Apr 18;31(4):683-698.e7.

doi: 10.1016/j.chembiol.2023.12.002. Epub 2023 Dec 26.

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

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

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

Cara Adolph et al. Cell Chem Biol. 2024.

. 2024 Apr 18;31(4):683-698.e7.

doi: 10.1016/j.chembiol.2023.12.002. Epub 2023 Dec 26.

Authors

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,.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests The authors declare no competing interests.

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions

LinkOut - more resources

Full Text Sources
- Elsevier Science
Medical
- Genetic Alliance
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Similar articles

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Abstract

Conflict of interest statement

Similar articles

MeSH terms

Substances

Related information

LinkOut - more resources

Full Text Sources

Medical