Journal Article

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

Holmes, Jessica R., Fields, Christopher J., Hergenrother, Paul J., Hung, Chien-Che, Lau, Gee W., Sinclair, Matt, Lee, Hyang Yeon, Ulrich, Rebecca J., Vasan, Archit K., Wen, Po-Chao, Tajkhorshid, Emad, Muñoz, Kristen A.

2024

Overview

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. Lolamicin, a novel antibiotic developed from a pyridinepyrazole precursor, exhibits potent activity against a broad range of Gram-negative multidrug-resistant clinical isolates, and good efficacy in mouse models of infection without inducing gut dysbiosis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 14/19 / 631/326/22/1290 / 631/326/2565/2134 / Animal models / Animals / Anti-Bacterial Agents - chemistry / Anti-Bacterial Agents - pharmacology / Antibiotics / Bacteria / Cell Line / Clinical isolates / Clostridioides difficile - drug effects / Clostridium Infections - drug therapy / Clostridium Infections - microbiology / Commensals / Disease Models, Animal / Drug Design / Drug Discovery / Drug Resistance, Multiple, Bacterial / E coli / FDA approval / Female / Gastrointestinal Microbiome - drug effects / Gram-negative bacteria / Gram-Negative Bacteria - drug effects / Gram-Negative Bacterial Infections - drug therapy / Gram-Negative Bacterial Infections - microbiology / Gram-positive bacteria / Gut microbiota / Homology / Humanities and Social Sciences / Humans / Infections / Intestinal microflora / Lipoproteins / Lipoproteins - metabolism / Male / Mice / Mice, Inbred C57BL / Microbiomes / multidisciplinary / Multidrug resistance / Nitriles - chemistry / Nitriles - pharmacology / Pathogens / Permeability / Protein Transport - drug effects / Proteins / Pyridines - chemistry / Pyridines - pharmacology / Science / Science (multidisciplinary) / Secondary infection / Sepsis - drug therapy / Sepsis - microbiology / Septicemia / Substrate Specificity / Symbiosis - drug effects / Taxonomy / Transportation systems