核糖体
抗菌剂
抗生素耐药性
铜绿假单胞菌
抗生素
大肠杆菌
微生物学
核糖体蛋白
23S核糖体RNA
核糖体RNA
核糖核酸
生物
细菌
遗传学
基因
作者
Kelvin J. Y. Wu,Ben I. C. Tresco,Antonio Ramkissoon,Elena V. Aleksandrova,Egor A. Syroegin,Dominic N. Y. See,Priscilla Liow,Georgia Dittemore,M. C. Z. Yu,Giambattista Testolin,Matthew J. Mitcheltree,Richard Y. Liu,Maxim S. Svetlov,Yury S. Polikanov,Andrew G. Myers
出处
期刊:Science
[American Association for the Advancement of Science (AAAS)]
日期:2024-02-15
卷期号:383 (6684): 721-726
被引量:15
标识
DOI:10.1126/science.adk8013
摘要
We report the design conception, chemical synthesis, and microbiological evaluation of the bridged macrobicyclic antibiotic cresomycin (CRM), which overcomes evolutionarily diverse forms of antimicrobial resistance that render modern antibiotics ineffective. CRM exhibits in vitro and in vivo efficacy against both Gram-positive and Gram-negative bacteria, including multidrug-resistant strains of Staphylococcus aureus , Escherichia coli , and Pseudomonas aeruginosa . We show that CRM is highly preorganized for ribosomal binding by determining its density functional theory–calculated, solution-state, solid-state, and (wild-type) ribosome-bound structures, which all align identically within the macrobicyclic subunits. Lastly, we report two additional x-ray crystal structures of CRM in complex with bacterial ribosomes separately modified by the ribosomal RNA methylases, chloramphenicol-florfenicol resistance (Cfr) and erythromycin-resistance ribosomal RNA methylase (Erm), revealing concessive adjustments by the target and antibiotic that permit CRM to maintain binding where other antibiotics fail.
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