Here, we characterized two novel amiloride derivatives in the search for antimicrobial compounds that target bacterial motility. Our two compounds were shown to inhibit flagellar motility at 10 μM across multiple strains: from nonpathogenic Escherichia coli with flagellar rotation driven by proton or chimeric sodium-powered stators, to proton-powered pathogenic E. coli (enterohemorrhagic E. coli or uropathogenic E. coli [EHEC or UPEC, respectively]), and finally, sodium-powered Vibrio alginolyticus .

Communications BiologyQ2 · BIOLOGY

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

Q2 · BIOLOGY

ArticleOA

Author: Berney, Michael ; Opel-Reading, Helen K ; Langer, Julian D ; Rhee, Kyu Y ; McNeil, Matthew B ; Tee, Zhi Shean ; Cheung, Chen-Yi ; Adolph, Cara ; Hasenoehrl, Erik J ; Preiss, Laura ; Meier, Thomas ; Tyndall, Joel D A ; Krause, Kurt ; Buckley, Benjamin J ; Hards, Kiel ; Cook, Gregory M ; Waller, Natalie ; Harold, Liam K ; Keighley, Laura ; Bujaroski, Richard S ; Kelso, Michael J ; Menorca, Ayana

AbstractIncreasing 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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Indication	Highest Phase	Country/Location	Organization	Date
Escherichia Coli Infections	Preclinical	Australia	The University of New South Wales	07 Sep 2021

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