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

Kristen A. Muñoz, Rebecca J. Ulrich, Archit K. Vasan, Matt Sinclair, Po-Chao Wen, Jessica R. Holmes, Hyang Yeon Lee, Chien-Che Hung, Christopher J. Fields, Emad Tajkhorshid, Gee W. Lau and Paul J. Hergenrother ()
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Kristen A. Muñoz: University of Illinois at Urbana-Champaign
Rebecca J. Ulrich: University of Illinois at Urbana-Champaign
Archit K. Vasan: University of Illinois at Urbana-Champaign
Matt Sinclair: University of Illinois at Urbana-Champaign
Po-Chao Wen: University of Illinois at Urbana-Champaign
Jessica R. Holmes: University of Illinois at Urbana-Champaign
Hyang Yeon Lee: University of Illinois at Urbana-Champaign
Chien-Che Hung: University of Illinois at Urbana-Champaign
Christopher J. Fields: University of Illinois at Urbana-Champaign
Emad Tajkhorshid: University of Illinois at Urbana-Champaign
Gee W. Lau: University of Illinois at Urbana-Champaign
Paul J. Hergenrother: University of Illinois at Urbana-Champaign

Nature, 2024, vol. 630, issue 8016, 429-436

Abstract: 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 infections1–3. 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.

Date: 2024
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DOI: 10.1038/s41586-024-07502-0

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