An Amiloride Derivative is Active Against the FF-ATP Synthase and Cytochrome Bd Oxidase of Mycobacterium Tuberculosis

Overview

Journal Commun Biol

Specialty Biology

Date 2022 Feb 25

PMID 35210534

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

Affiliations

Soon will be listed here.

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 FF-ATP synthase, depletes ATP, and affects the entry of acetyl-CoA into the Krebs cycle. HM2-16F synergizes with the cytochrome bcc-aa 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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