An amiloride derivative is active against the F1Fo-ATP synthase and cytochrome bd oxidase of Mycobacterium tuberculosis.
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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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| Authors | Kiel Hards, Chen-Yi Cheung, Natalie Waller, Cara Adolph, Laura Keighley, Zhi Shean Tee, Liam K Harold, Ayana Menorca, Richard S Bujaroski, Benjamin J Buckley, Joel D A Tyndall, Matthew B McNeil, Kyu Y Rhee, Helen K Opel-Reading, Kurt Krause, Laura Preiss, Julian D Langer, Thomas Meier, Erik J Hasenoehrl, Michael Berney, Michael J Kelso, Gregory M Cook |
| Journal | Communications biology (Commun Biol) Vol. 5 Issue 1 Pg. 166 (02 24 2022) ISSN: 2399-3642 [Electronic] England |
| PMID | 35210534 (Publication Type: Journal Article) |
| Copyright | © 2022. The Author(s). |
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