美国伊利诺伊大学香槟分校Paul J. Hergenrother团队开发出保护肠道微生物群的革兰氏阴性选择性抗生素。相关论文于2024年5月29日在线发表在《自然》杂志上。

研究人员报告了一种针对脂蛋白转运系统的革兰氏阴性特异性抗生素——lolamicin 的设计和发现。lolamicin对 130 多种耐多药临床分离菌具有活性，在多种小鼠急性肺炎和败血症感染模型中显示出疗效，并能保护小鼠肠道微生物群，防止艰难梭菌的二次感染。

lolamicin对致病性革兰氏阴性菌的选择性杀灭作用，是致病性细菌与普通细菌目标序列同源性较低的结果，这种双重选择性策略可以作为开发其他保护微生物群抗生素的蓝图。

据悉，由革兰氏阴性病原体引起的感染越来越普遍，通常采用广谱抗生素治疗，结果导致肠道微生物群紊乱，容易继发感染。目前亟需对革兰氏阴性菌和致病菌都有选择性的抗生素。

附：英文原文

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

Author: Muoz, 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.

Issue&Volume: 2024-05-29

Abstract: 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 infections1,2,3. 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.

DOI: 10.1038/s41586-024-07502-0

Source: https://www.nature.com/articles/s41586-024-07502-0