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  An amiloride derivative is active against the F1Fo-ATP synthase and cytochrome bd oxidase of Mycobacterium tuberculosis

Hards, K., Cheung, C.-Y., Waller, N., Adolph, C., Keighley, L., Tee, Z. S., et al. (2022). An amiloride derivative is active against the F1Fo-ATP synthase and cytochrome bd oxidase of Mycobacterium tuberculosis. Communications Biology, 5(1): 166. doi:10.1038/s42003-022-03110-8.

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Hards, Kiel1, 2, Author
Cheung, Chen-Yi1, Author
Waller, Natalie1, Author
Adolph, Cara1, Author
Keighley, Laura1, Author
Tee, Zhi Shean1, Author
Harold, Liam K.1, 2, Author
Menorca, Ayana1, Author
Bujaroski, Richard S.3, 4, Author
Buckley, Benjamin J.3, 4, Author
Tyndall, Joel D.A.5, Author
McNeil, Matthew B.1, 2, Author
Rhee, Kyu Y.6, Author
Opel-Reading, Helen K.7, Author
Krause, Kurt2, Author
Preiss, Laura8, 9, Author           
Langer, Julian David10, 11, Author           
Meier, Thomas12, 13, Author
Hasenoehrl, Erik J.14, Author
Berney, Michael14, Author
Kelso, Michael J.3, 4, AuthorCook, Gregory M.1, 2, Author more..
Affiliations:
1Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand, ou_persistent22              
2Maurice Wilkins Centre for Molecular Biodiscovery, The University of Otago, Dunedin, New Zealand, ou_persistent22              
3Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, Australia, ou_persistent22              
4Illawarra Health and Medical Research Institute, Wollongong, Australia, ou_persistent22              
5School of Pharmacy, University of Otago, Dunedin, New Zealand, ou_persistent22              
6Weill Department of Medicine, Weill Cornell Medical College, New York, NY, USA, ou_persistent22              
7Department of Biochemistry, University of Otago, Dunedin, New Zealand, ou_persistent22              
8Department of Structural Biology, Max Planck Institute of Biophysics, Max Planck Society, ou_2068291              
9Octapharma Biopharmaceuticals GmbH, Heidelberg, Germany, ou_persistent22              
10Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society, ou_2068290              
11Proteomics and Mass Spectrometry, Max Planck Institute of Biophysics, Max Planck Society, ou_persistent22              
12Department of Life Sciences, Imperial College London, London, UK, ou_persistent22              
13Private University in the Principality of Liechtenstein, Triesen, Liechtenstein, ou_persistent22              
14Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, NY, USA, ou_persistent22              

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 Abstract: Increasing antimicrobial resistance compels the search for next-generation inhibitors with differing or multiple molecular targets. In this regard, energy conservation in Mycobacterium tuberculosis has been clinically validated as a promising new drug target for combatting drug-resistant strains of M. tuberculosis. Here, we show that HM2-16F, a 6-substituted derivative of the FDA-approved drug amiloride, is an anti-tubercular inhibitor with bactericidal properties comparable to the FDA-approved drug bedaquiline (BDQ; Sirturo®) and inhibits the growth of bedaquiline-resistant mutants. We show that HM2-16F weakly inhibits the F1Fo-ATP synthase, depletes ATP, and affects the entry of acetyl-CoA into the Krebs cycle. HM2-16F synergizes with the cytochrome bcc-aa3 oxidase inhibitor Q203 (Telacebec) and co-administration with Q203 sterilizes in vitro cultures in 14 days. Synergy with Q203 occurs via direct inhibition of the cytochrome bd oxidase by HM2-16F. This study shows that amiloride derivatives represent a promising discovery platform for targeting energy generation in drug-resistant tuberculosis.

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Language(s): eng - English
 Dates: 2021-07-142022-02-032022-02-24
 Publication Status: Published online
 Pages: 11
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1038/s42003-022-03110-8
PMID: 35210534
 Degree: -

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Title: Communications Biology
Source Genre: Journal
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Publ. Info: London : Springer Nature
Pages: - Volume / Issue: 5 (1) Sequence Number: 166 Start / End Page: - Identifier: ISSN: 2399-3642
CoNE: https://pure.mpg.de/cone/journals/resource/2399-3642