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

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Preiss,  Laura
Department of Structural Biology, Max Planck Institute of Biophysics, Max Planck Society;
Octapharma Biopharmaceuticals GmbH, Heidelberg, Germany;

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Langer,  Julian David
Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society;
Proteomics and Mass Spectrometry, Max Planck Institute of Biophysics, Max Planck Society;

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Citation

Hards, K., Cheung, C.-Y., Waller, N., Adolph, C., Keighley, L., Tee, Z. S., et al. (2022). An amiloride derivative is active against the F1Fo-ATP synthase and cytochrome bd oxidase of Mycobacterium tuberculosis. Communications Biology, 5(1): 166. doi:10.1038/s42003-022-03110-8.


Cite as: https://hdl.handle.net/21.11116/0000-000A-0E3D-4
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.