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

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. As such, there is a critical need for antibiotics that not only are selective for gram-negative bacteria over gram-positive bacteria, but also selective 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 over 130 multidrug-resistant clinical isolates, shows efficacy in multiple acute pneumonia and septicemia murine infection models, and spares the gut microbiome in mice, preventing secondary Clostridioides difficile infection. 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.