Synthesis and Evaluation of Pseudomonas aeruginosa ATP Synthase Inhibitors.
Synthesis and Evaluation of Pseudomonas aeruginosa ATP Synthase Inhibitors.
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DOI：
10.1021/acsomega.2c03127
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发表时间：
2022-08-16
期刊：
影响因子：
4.1
通讯作者：
Wolfe, Amanda L.
中科院分区：
文献类型：
--
作者：
Ciprich, John F.;Buckhalt, Alexander J. E.;Carroll, Lane L.;Chen, David;DeFiglia, Steven A.;McConnell, Riley S.;Parmar, Dhruvi J.;Pistor, Olivia L.;Rao, Aliyah B.;Rubin, M. Lillian;Volk, Grace E.;Steed, P. Ryan;Wolfe, Amanda L.
迫切需要具有独特生物靶点的新抗生素来对抗越来越多的耐药细菌病原体。ATP合酶是一种在所有生命中发现的关键蛋白质，由于抗结核药物贝达喹啉的成功，最近已成为抗生素开发的目标，尽管许多小组致力于开发靶向细菌ATP合酶的药物，但很少有人成功地特异性抑制铜绿假单胞菌（PA）ATP合酶。PA是全球耐药医院感染的主要原因之一，由于其对最常用抗生素的各种抗生素耐药机制，治疗极具挑战性。在此，我们详细介绍了一系列C1/C2喹啉类似物的合成和评估，以评估它们抑制PA ATP合酶并作为针对野生型PA的抗生素的能力。从这项调查中，我们发现了六种化合物能够抑制PA ATP合酶在体外显示，庞大的/疏水的C1/C2取代是优选的。最强的抑制剂显示IC 50为10 μg/mL，并且相对于对照，PA ATP合酶的活性降低至24%。虽然没有一种化合物能够抑制细胞培养物中的野生型PA，但当外膜的渗透性增加或外排被敲除时，两种化合物显示出改善的PA生长抑制，从而证明这些化合物可以进一步开发成有效的抗生素。
New antibiotics with unique biological targets are desperately needed to combat the growing number of resistant bacterial pathogens. ATP synthase, a critical protein found in all life, has recently become a target of interest for antibiotic development due to the success of the anti-tuberculosis drug bedaquiline, and while many groups have worked on developing drugs to target bacterial ATP synthase, few have been successful at inhibiting Pseudomonas aeruginosa (PA) ATP synthase specifically. PA is one of the leading causes of resistant nosocomial infections across the world and is extremely challenging to treat due to its various antibiotic resistance mechanisms for most commonly used antibiotics. Herein, we detail the synthesis and evaluation of a series of C1/C2 quinoline analogues for their ability to inhibit PA ATP synthase and act as antibiotics against wild-type PA. From this survey, we found six compounds capable of inhibiting PA ATP synthase in vitro showing that bulky/hydrophobic C1/C2 substitutions are preferred. The strongest inhibitor showed an IC50 of 10 μg/mL and decreased activity of PA ATP synthase to 24% relative to the control. While none of the compounds were able to inhibit wild-type PA in cell culture, two showed improved inhibition of PA growth when permeability of the outer membrane was increased or efflux was knocked out, thus demonstrating that these compounds could be further developed into efficacious antibiotics.
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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：
5.3
作者：
Perlmutter SJ;Geddes EJ;Drown BS;Motika SE;Lee MR;Hergenrother PJ
通讯作者：
Hergenrother PJ
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：
64.8
作者：
Richter MF;Drown BS;Riley AP;Garcia A;Shirai T;Svec RL;Hergenrother PJ
通讯作者：
Hergenrother PJ
影响因子：
5.2
作者：
Arai H
通讯作者：
Arai H