An antibiotic preorganized for ribosomal binding overcomes antimicrobial resistance

• 成果类型: Article
• 署名作者: Wu, Kelvin J. Y.; Tresco, Ben I. C.; Ramkissoon, Antonio; Aleksandrova, Elena V.; Syroegin, Egor A.; See, Dominic N. Y.; Liow, Priscilla; Dittemore, Georgia A.; Yu, Meiyi; Testolin, Giambattista; Mitcheltree, Matthew J.; Liu, Richard Y.; Svetlov, Maxim S.; Polikanov, Yury S.; Myers, Andrew G.
• 署名单位: Harvard University; University of Illinois System; University of Illinois Chicago; University of Illinois Chicago Hospital; University of Illinois System; University of Illinois Chicago; University of Illinois Chicago Hospital; University of Illinois System; University of Illinois Chicago; University of Illinois Chicago Hospital; Merck & Company; Merck & Company USA
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9615
• DOI: 10.1126/science.adk8013
• 发表日期: 2024-02-16
• 页码: 721-726
• 关键词: peptidyl transferase center; structural basis; lincosamides; streptogramin; clindamycin

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.