An amiloride derivative is active against the F1Fo-ATP synthase and cytochrome bd oxidase of Mycobacterium tuberculosis
Kiel Hards, Chen‐Yi Cheung, Natalie J.E. Waller, Cara Adolph, Laura M. 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 L. Krause, Laura Preiß, Julian D. Langer, Thomas Meier, Erik Hasenoehrl, Michael Berney, Michael J. Kelso, Gregory M. Cook
Abstract
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 F 1 F o -ATP synthase, depletes ATP, and affects the entry of acetyl-CoA into the Krebs cycle. HM2-16F synergizes with the cytochrome bcc-aa 3 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.