Quinoline Compounds Targeting the c-Ring of ATP Synthase Inhibit Drug-Resistant Pseudomonas aeruginosa.
Quinoline Compounds Targeting the c-Ring of ATP Synthase Inhibit Drug-Resistant Pseudomonas aeruginosa.
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DOI：
10.1021/acsinfecdis.3c00317
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发表时间：
2023-12-08
影响因子：
5.3
通讯作者：
Steed PR
中科院分区：
文献类型：
--
作者：
Fraunfelter VM;Pugh BA;Williams APL;Ward KT;Jackson DO;Austin M;Ciprich JF;Dippy L;Dunford J;Edwards GN;Glass E;Handy KM;Kellogg CN;Llewellyn K;Nyberg KQ;Shepard SJ;Thomas C;Wolfe AL;Steed PR
铜绿假单胞菌 (PA) 是一种革兰氏阴性生物膜形成细菌和机会性病原体。 PA 日益增长的耐药性是一个严重的威胁，因此需要发现新型抗生素，最好具有以前未充分探索的作用机制。由于它们在细胞代谢中的核心作用，细菌生物能过程作为药物靶点越来越受到关注，特别是随着 ATP 合酶抑制剂贝达喹啉成功治疗耐药结核病。与结核分枝杆菌一样，即使在厌氧条件下，PA 也需要 F1Fo ATP 合酶才能生长，这使得 PA ATP 合酶成为治疗耐药感染的理想药物靶点。在之前的工作中，我们对抑制 PA 中 ATP 合成活性的喹啉化合物进行了初步筛选。在本研究中，我们报告了其他喹啉衍生物，包括一种在体外具有增强的抗 PA ATP 合酶效力和对耐药 PA 的抗菌活性的衍生物。此外，通过在大肠杆菌中表达 PA ATP 合酶，我们发现膜嵌入转子环上 H+ 结合位点的突变改变了所报道的喹啉化合物的抑制作用。鉴定出有效的抑制剂及其在 ATP 合酶上可能的结合位点，能够进一步开发有前景的喹啉衍生物，使其成为治疗耐药性 PA 感染的可行方法。
Pseudomonas aeruginosa (PA) is a Gram-negative, biofilm-forming bacterium and an opportunistic pathogen. The growing drug resistance of PA is a serious threat that necessitates the discovery of novel antibiotics, ideally with previously underexplored mechanisms of action. Due to their central role in cell metabolism, bacterial bioenergetic processes are of increasing interest as drug targets, especially with the success of the ATP synthase inhibitor bedaquiline to treat drug-resistant tuberculosis. Like Mycobacterium tuberculosis, PA requires F1Fo ATP synthase for growth, even under anaerobic conditions, making the PA ATP synthase an ideal drug target for the treatment of drug-resistant infection. In previous work, we conducted an initial screen for quinoline compounds that inhibit ATP synthesis activity in PA. In the present study, we report additional quinoline derivatives, including one with increased potency against PA ATP synthase in vitro and antibacterial activity against drug-resistant PA. Moreover, by expressing the PA ATP synthase in Escherichia coli, we show that mutations in the H+ binding site on the membrane-embedded rotor ring alter inhibition by the reported quinoline compounds. Identification of a potent inhibitor and its probable binding site on ATP synthase enables further development of promising quinoline derivatives into a viable treatment for drug-resistant PA infection.
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影响因子：
4.6
作者：
Milgrom YM;Duncan TM
通讯作者：
Duncan TM
影响因子：
4.3
作者：
Shrestha, Rashmi K.;Founds, Michael W.;Steed, P. Ryan
通讯作者：
Steed, P. Ryan
影响因子：
5.9
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
通讯作者：
Cook GM
影响因子：
5.2
作者：
Arai H
通讯作者：
Arai H
DOI：
10.1016/0005-2728(85)90254-3
发表时间：
1985-01-01
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
PERLIN, DS;LATCHNEY, LR;SENIOR, AE
通讯作者：
SENIOR, AE