粘菌素
多粘菌素
鲍曼不动杆菌
抗菌剂
铜绿假单胞菌
化学
抗菌活性
MCR-1型
微生物学
抗生素
大肠杆菌
肺炎克雷伯菌
细菌
抗生素耐药性
多粘菌素B
多重耐药
肠杆菌科
生物
生物化学
遗传学
基因
作者
Jørgen Jørgensen,Elnaz Harifi Mood,Anne Sofie Holst Knap,Svend Erik Nielsen,Peter E. Nielsen,Dorota Żabicka,Carina Matias,Ilona Domračeva,Fredrik Björkling,Henrik Franzyk
标识
DOI:10.1021/acs.jmedchem.3c01908
摘要
In view of the increased prevalence of antimicrobial resistance among human pathogens, antibiotics against multidrug-resistant (MDR) bacteria are in urgent demand. In particular, the rapidly emerging resistance to last-resort antibiotic colistin, used for severe Gram-negative MDR infections, is critical. Here, a series of polymyxins containing unnatural amino acids were explored, and some analogues exhibited excellent antibacterial activity against Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. Hydrophobicity of the compounds within this series (as measured by retention in reversed-phase analytical HPLC) exhibited a discernible correlation with their antimicrobial activity. This trend was particularly pronounced for colistin-resistant pathogens. The most active compounds demonstrated competitive activity against a panel of Gram-negative pathogens, while exhibiting low in vitro cytotoxicity. Importantly, most of these hits also retained (or even had increased) potency against colistin-susceptible strains. These findings infer that fine-tuning hydrophobicity may enable the design of polymyxin analogues with favorable activity profiles.
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