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An amiloride derivative is active against the F₁F_o-ATP synthase and cytochrome bd oxidase of Mycobacterium tuberculosis.

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 F₁F_o-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.

SUBMITTER: Hards K

PROVIDER: S-EPMC8873251 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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An amiloride derivative is active against the F<sub>1</sub>F<sub>o</sub>-ATP synthase and cytochrome bd oxidase of Mycobacterium tuberculosis.

Hards Kiel K Cheung Chen-Yi CY Waller Natalie N Adolph Cara C Keighley Laura L Tee Zhi Shean ZS Harold Liam K LK Menorca Ayana A Bujaroski Richard S RS Buckley Benjamin J BJ Tyndall Joel D A JDA McNeil Matthew B MB Rhee Kyu Y KY Opel-Reading Helen K HK Krause Kurt K Preiss Laura L Langer Julian D JD Meier Thomas T Hasenoehrl Erik J EJ Berney Michael M Kelso Michael J MJ Cook Gregory M GM

Communications biology 20220224 1

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 ...[more]

PMID: 35210534

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Project description:The cydAB genes from Mycobacterium smegmatis have been cloned and characterized. The cydA and cydB genes encode the two subunits of a cytochrome bd oxidase belonging to the widely distributed family of quinol oxidases found in prokaryotes. The cydD and cydC genes located immediately downstream of cydB encode a putative ATP-binding cassette-type transporter. At room temperature, reduced minus oxidized difference spectra of membranes purified from wild-type M. smegmatis displayed spectral features that are characteristic of the gamma-proteobacterial type cytochrome bd oxidase. Inactivation of cydA or cydB by insertion of a kanamycin resistance marker resulted in loss of d-heme absorbance at 631 nm. The d-heme could be restored by transformation of the M. smegmatis cyd mutants with a replicating plasmid carrying the highly homologous cydABDC gene cluster from Mycobacterium tuberculosis. Inactivation of cydA had no effect on the ability of M. smegmatis to exit from stationary phase at 37 or 42 degrees C. The growth rate of the cydA mutant was tested under oxystatic conditions. Although no discernible growth defect was observed under moderately aerobic conditions (9.2 to 37.5 x 10(2) Pa of pO(2) or 5 to 21% air saturation), the mutant displayed a significant growth disadvantage when cocultured with the wild type under extreme microaerophilia (0.8 to 1.7 x 10(2) Pa of pO(2) or 0.5 to 1% air saturation). These observations were in accordance with the two- to threefold increase in cydAB gene expression observed upon reduction of the pO(2) of the growth medium from 21 to 0.5% air saturation and with the concomitant increase in d-heme absorbance in spectra of membranes isolated from wild-type M. smegmatis cultured at 1% air saturation. Finally, the cydA mutant displayed a competitive growth disadvantage in the presence of the terminal oxidase inhibitor, cyanide, when cocultured with wild type at 21% air saturation in an oxystat. In conjunction with these findings, our results suggest that cytochrome bd is an important terminal oxidase in M. smegmatis.

Dataset Information

An amiloride derivative is active against the F₁F_o-ATP synthase and cytochrome bd oxidase of Mycobacterium tuberculosis.

Publications

An amiloride derivative is active against the F<sub>1</sub>F<sub>o</sub>-ATP synthase and cytochrome bd oxidase of Mycobacterium tuberculosis.

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Dataset Information

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

Publications

An amiloride derivative is active against the F<sub>1</sub>F<sub>o</sub>-ATP synthase and cytochrome bd oxidase of Mycobacterium tuberculosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

An amiloride derivative is active against the F₁F_o-ATP synthase and cytochrome bd oxidase of Mycobacterium tuberculosis.