流出
鲍曼不动杆菌
铜绿假单胞菌
利奈唑啉
化学
微生物学
细菌外膜
细菌
革兰氏阴性菌
大肠杆菌
革兰氏阳性菌
抗生素
生物
生物化学
金黄色葡萄球菌
万古霉素
遗传学
基因
作者
Ziwei Hu,Inga V. Leus,Brinda Chandar,Brad Sherborne,Quentin P. Avila,Valentin V. Rybenkov,Helen I. Zgurskaya,Adam S. Duerfeldt
标识
DOI:10.1021/acs.jmedchem.2c01349
摘要
The clinical success of linezolid for treating Gram-positive infections paired with the high conservation of bacterial ribosomes predicts that if oxazolidinones were engineered to accumulate in Gram-negative bacteria, then this pharmacological class would find broad utility in eradicating infections. Here, we report an investigative study of a strategically designed library of oxazolidinones to determine the effects of molecular structure on accumulation and biological activity. Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa strains with varying degrees of compromise (in efflux and outer membrane) were used to identify motifs that hinder permeation across the outer membrane and/or enhance efflux susceptibility broadly and specifically between species. The results illustrate that small changes in molecular structure are enough to overcome the efflux and/or permeation issues of this scaffold. Three oxazolidinone analogues (3e, 8d, and 8o) were identified that exhibit activity against all three pathogens assessed, a biological profile not observed for linezolid.
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