Citation

BibTex format

@article{Hards:2022:10.1038/s42003-022-03110-8,
author = {Hards, K and Cheung, C-Y and Waller, N and Adolph, C and Keighley, L and Tee, ZS and Harold, LK and Menorca, A and Bujaroski, RS and Buckley, BJ and Tyndall, JDA and McNeil, MB and Rhee, KY and Opel-Reading, HK and Krause, K and Preiss, L and Langer, JD and Meier, T and Hasenoehrl, EJ and Berney, M and Kelso, MJ and Cook, GM},
doi = {10.1038/s42003-022-03110-8},
journal = {Commun Biol},
title = {An amiloride derivative is active against the F1Fo-ATP synthase and cytochrome bd oxidase of Mycobacterium tuberculosis.},
url = {http://dx.doi.org/10.1038/s42003-022-03110-8},
volume = {5},
year = {2022}
}

RIS format (EndNote, RefMan)

TY  - JOUR
AB - 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.
AU - Hards,K
AU - Cheung,C-Y
AU - Waller,N
AU - Adolph,C
AU - Keighley,L
AU - Tee,ZS
AU - Harold,LK
AU - Menorca,A
AU - Bujaroski,RS
AU - Buckley,BJ
AU - Tyndall,JDA
AU - McNeil,MB
AU - Rhee,KY
AU - Opel-Reading,HK
AU - Krause,K
AU - Preiss,L
AU - Langer,JD
AU - Meier,T
AU - Hasenoehrl,EJ
AU - Berney,M
AU - Kelso,MJ
AU - Cook,GM
DO - 10.1038/s42003-022-03110-8
PY - 2022///
TI - An amiloride derivative is active against the F1Fo-ATP synthase and cytochrome bd oxidase of Mycobacterium tuberculosis.
T2 - Commun Biol
UR - http://dx.doi.org/10.1038/s42003-022-03110-8
UR - https://www.ncbi.nlm.nih.gov/pubmed/35210534
VL - 5
ER -