An amiloride derivative is active against the F(1)F(o)-ATP synthase and cytochrome bd oxidase of Mycobacterium tuberculosis.
An amiloride derivative is active against the F(1)F(o)-ATP synthase and cytochrome bd oxidase of Mycobacterium tuberculosis.
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DOI：
10.1038/s42003-022-03110-8
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发表时间：
2022-02-24
影响因子：
5.9
通讯作者：
Cook GM
中科院分区：
文献类型：
--
作者：
Hards K;Cheung CY;Waller N;Adolph C;Keighley L;Tee ZS;Harold LK;Menorca A;Bujaroski RS;Buckley BJ;Tyndall JDA;McNeil MB;Rhee KY;Opel-Reading HK;Krause K;Preiss L;Langer JD;Meier T;Hasenoehrl EJ;Berney M;Kelso MJ;Cook GM
抗菌素耐药性的增加迫使人们寻找具有不同或多个分子靶点的下一代抑制剂。在这方面，结核分枝杆菌的能量守恒已被临床验证为对抗耐药结核分枝杆菌菌株的有前途的新药物靶标。结核在这里，我们表明HM 2 - 16 F，FDA批准的药物阿米洛利的6-取代衍生物，是一种抗结核抑制剂，具有与FDA批准的药物贝达喹啉（BDQ; Sirturo®）相当的杀菌特性，并抑制贝达喹啉耐药突变体的生长。我们发现，HM 2 - 16 F弱抑制F1 Fo-ATP合酶，消耗ATP，并影响乙酰辅酶A进入克雷布斯循环。HM 2 - 16 F与细胞色素bcc-aa 3氧化酶抑制剂Q203（Telacebec）协同作用，与Q203联合给药可在14天内对体外培养物灭菌。通过HM 2 - 16 F直接抑制细胞色素bd氧化酶，与Q203产生协同作用。这项研究表明，阿米洛利衍生物代表了一个有前途的发现平台，针对耐药结核病的能量产生。FDA批准的药物阿米洛利的衍生物可以通过干扰细菌能量守恒来消除体外耐药结核分枝杆菌。
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. Derivatives of the FDA-approved drug, amiloride, can eliminate drug-resistant Mycobacterium tuberculosis in vitro by interfering with bacterial energy conservation.
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影响因子：
7.3
作者：
Buckley BJ;Aboelela A;Minaei E;Jiang LX;Xu Z;Ali U;Fildes K;Cheung CY;Cook SM;Johnson DC;Bachovchin DA;Cook GM;Apte M;Huang M;Ranson M;Kelso MJ
通讯作者：
Kelso MJ
影响因子：
16.6
作者：
Koul, Anil;Vranckx, Luc;Dhar, Neeraj;Gohlmann, Hinrich W. H.;Oezdemir, Emre;Neefs, Jean-Marc;Schulz, Melanie;Lu, Ping;Mortz, Ejvind;McKinney, John D.;Andries, Koen;Bald, Dirk
通讯作者：
Bald, Dirk
影响因子：
64.8
作者：
Guo, Hui;Courbon, Gautier M.;Rubinstein, John L.
通讯作者：
Rubinstein, John L.
DOI：
10.1016/s2213-2600(14)70031-1
发表时间：
2014-04
期刊：
The Lancet. Respiratory medicine
影响因子：
--
作者：
Dheda K;Gumbo T;Gandhi NR;Murray M;Theron G;Udwadia Z;Migliori GB;Warren R
通讯作者：
Warren R
影响因子：
64.5
作者：
Baconguis I;Bohlen CJ;Goehring A;Julius D;Gouaux E
通讯作者：
Gouaux E