Amine Basicity of Quinoline ATP Synthase Inhibitors Drives Antibacterial Activity against Pseudomonas aeruginosa.
Amine Basicity of Quinoline ATP Synthase Inhibitors Drives Antibacterial Activity against Pseudomonas aeruginosa.
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DOI：
10.1021/acsmedchemlett.3c00480
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发表时间：
2024-01-11
影响因子：
4.2
通讯作者：
Wolfe, Amanda L.
中科院分区：
文献类型：
--
作者：
Ward, Katie T.;Williams, Alexander P. L.;Blair, Courtney A.;Chatterjee, Ananya M.;Karthikeyan, Abirami;Roper, Addison S.;Kellogg, Casey N.;Steed, P. Ryan;Wolfe, Amanda L.
关键词：
铜绿假单胞菌 (PA) 是一种革兰氏阴性病原体，是医院感染的常见原因，特别是在免疫功能低下和囊性纤维化患者中。 PA 由于其紧密堆积的阴离子脂多糖外膜、外排泵和形成生物膜的能力，对许多当前处方的抗生素具有本质上的抵抗力。 PA 可以通过突变和水平基因转移获得额外的抗性。 PA ATP 合酶是抗生素开发的一个有吸引力的靶标，因为即使在发酵条件下，它对于细胞生存也至关重要。此前，我们开发了两种喹啉先导化合物，它们能够选择性抑制PA ATP合酶，并可作为针对多重耐药PA的抗菌剂。在此，我们通过18种喹啉衍生物的合成和评价，对先导化合物进行构效关系分析。这些化合物充当新的抗菌剂，同时提供对促进细胞进入同时维持 PA ATP 合酶抑制所需的物理特性的平衡的深入了解。
Pseudomonas aeruginosa (PA), a Gram-negative pathogen, is a common cause of nosocomial infections, especially in immunocompromised and cystic fibrosis patients. PA is intrinsically resistant to many currently prescribed antibiotics due to its tightly packed, anionic lipopolysaccharide outer membrane, efflux pumps, and ability to form biofilms. PA can acquire additional resistance through mutation and horizontal gene transfer. PA ATP synthase is an attractive target for antibiotic development because it is essential for cell survival even under fermentation conditions. Previously, we developed two lead quinoline compounds that were capable of selectively inhibiting PA ATP synthase and acting as antibacterial agents against multidrug-resistant PA. Herein we conduct a structure–activity relationship analysis of the lead compounds through the synthesis and evaluation of 18 quinoline derivatives. These compounds function as new antibacterial agents while providing insight into the balance of physical properties needed to promote cellular entry while maintaining PA ATP synthase inhibition.
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