A Gram-negative-selective antibiotic that spares the gut microbiome

• 成果类型: Article
• 署名作者: Munoz, Kristen A.; Ulrich, Rebecca J.; Vasan, Archit K.; Sinclair, Matt; Wen, Po-Chao; Holmes, Jessica R.; Lee, Hyang Yeon; Hung, Chien-Che; Fields, Christopher J.; Tajkhorshid, Emad; Lau, Gee W.; Hergenrother, Paul J.
• 署名单位: University of Illinois System; University of Illinois Urbana-Champaign; University of Illinois System; University of Illinois Urbana-Champaign; University of Illinois System; University of Illinois Urbana-Champaign; University of Illinois System; University of Illinois Urbana-Champaign; University of Illinois System; University of Illinois Urbana-Champaign; University of Illinois System; University of Illinois Urbana-Champaign; University of Illinois System; University of Illinois Urbana-Champaign; University of Illinois System; University of Illinois Urbana-Champaign; University of Illinois System; University of Illinois Urbana-Champaign
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5262
• DOI: 10.1038/s41586-024-07502-0
• 发表日期: 2024-06-13
• 页码: 429-+
• 关键词: molecular-dynamics; escherichia-coli; outer-membrane; software news; lipoproteins; bacteroides; management; resistance; inhibitors; update

摘要

Infections caused by Gram-negative pathogens are increasingly prevalent and are typically treated with broad-spectrum antibiotics, resulting in disruption of the gut microbiome and susceptibility to secondary infections(1-3). There is a critical need for antibiotics that are selective both for Gram-negative bacteria over Gram-positive bacteria, as well as for pathogenic bacteria over commensal bacteria. Here we report the design and discovery of lolamicin, a Gram-negative-specific antibiotic targeting the lipoprotein transport system. Lolamicin has activity against a panel of more than 130 multidrug-resistant clinical isolates, shows efficacy in multiple mouse models of acute pneumonia and septicaemia infection, and spares the gut microbiome in mice, preventing secondary infection with Clostridioides difficile. The selective killing of pathogenic Gram-negative bacteria by lolamicin is a consequence of low sequence homology for the target in pathogenic bacteria versus commensals; this doubly selective strategy can be a blueprint for the development of other microbiome-sparing antibiotics.