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

Author:

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

Abstract

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.

Publisher

Springer Science and Business Media LLC

Subject

General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)

Reference51 articles.

1. World Health Organization. Global Tuberculosis Report 2019 (Geneva: World Health Organization, 2019).

2. Dheda, K. et al. Global control of tuberculosis: from extensively drug-resistant to untreatable tuberculosis. Lancet Respir. Med. 2, 321–338 (2014).

3. World Health Organization. Guidelines for the Treatment of Tuberculosis: Fourth Edition (World Health Organization, 2010).

4. World Health Organization. Guidelines for the Programmatic Management of Drug-Resistant Tuberculosis: Emergency Update 2008 (Geneva: World Health Organization, 2008).

5. Jones, D. Tuberculosis success. Nat. Rev. Drug Discov. 12, 175–176 (2013).

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