鲍曼不动杆菌
铜绿假单胞菌
细菌
化学
抗菌剂
微生物学
抗菌活性
体内
抗生素
革兰氏阴性菌
多重耐药
药代动力学
抗菌剂
药理学
生物
生物化学
大肠杆菌
生物技术
基因
遗传学
作者
Yinyong Zhang,Dan Zhang,Wenzhi Zhao,Hongyuan Li,Zhengliang Lü,Bin Guo,Xin Meng,Xian‐Li Zhou,Yushe Yang
标识
DOI:10.1021/acs.jmedchem.4c00018
摘要
G0775, an arylomycin-type SPase I inhibitor that is being evaluated in a preclinical study, exhibited potent antibacterial activities against some Gram-negative bacteria but meanwhile suffered defects such as a narrow antibacterial spectrum and poor pharmacokinetic properties. Herein, systematic structural modifications were carried out, including optimization of the macrocyclic skeleton, warheads, and lipophilic regions. The optimization culminated in the discovery of 138f, which showed more potent activity and a broader spectrum against clinically isolated carbapenem-resistant Gram-negative bacteria, especially against Acinetobacter baumannii and Pseudomonas aeruginosa. 162, the free amine of 138f, exhibited an excellent pharmacokinetic profile in rats. In a neutropenic mouse thigh model of infection with multidrug-resistant P. aeruginosa, the potent in vivo antibacterial efficacy of 162 was confirmed and superior to that of G0775 (3.5-log decrease vs 1.1-log decrease in colony-forming unit (CFU)). These results support 162 as a potential antimicrobial agent for further research.
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