化学
鲍曼不动杆菌
连接器
肺炎克雷伯菌
抗菌剂
儿茶酚
组合化学
细菌
体内
抗菌活性
头孢菌素
革兰氏阴性菌
抗菌剂
微生物学
抗生素
生物化学
铜绿假单胞菌
有机化学
大肠杆菌
生物
生物技术
遗传学
基因
计算机科学
操作系统
作者
Fangjun Liu,Qunhuan Kou,Hongyuan Li,Yangzhi Cao,Meng Chen,Xin Meng,Yinyong Zhang,Ting Wang,Hui Wang,Dan Zhang,Yushe Yang
标识
DOI:10.1021/acs.jmedchem.4c00265
摘要
Cefiderocol is the first approved catechol-conjugated cephalosporin against multidrug-resistant Gram-negative bacteria, while its application was limited by poor chemical stability associated with the pyrrolidinium linker, moderate potency against Klebsiella pneumoniae and Acinetobacter baumannii, intricate procedures for salt preparation, and potential hypersensitivity. To address these issues, a series of novel catechol-conjugated derivatives were designed, synthesized, and evaluated. Extensive structure-activity relationships and structure-metabolism relationships (SMR) were conducted, leading to the discovery of a promising compound 86b (Code no. YFJ-36) with a new thioether linker. 86b exhibited superior and broad-spectrum in vitro antibacterial activity, especially against A. baumannii and K. pneumoniae, compared with cefiderocol. Potent in vivo efficacy was observed in a murine systemic infection model. Furthermore, the physicochemical stability of 86b in fluid medium at pH 6-8 was enhanced. 86b also reduced potential the risk of allergy owing to the quaternary ammonium linker. The improved properties of 86b supported its further research and development.
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