2. Academic Validation
  3. A Gram-negative-selective antibiotic that spares the gut microbiome

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

  • Nature. 2024 Jun;630(8016):429-436. doi: 10.1038/s41586-024-07502-0.
Kristen A Muñoz 1 2,  Rebecca J Ulrich 1 2,  Archit K Vasan 3 4 5,  Matt Sinclair 3 4,  Po-Chao Wen 3 4 5,  Jessica R Holmes 6,  Hyang Yeon Lee 1 2,  Chien-Che Hung 7 8,  Christopher J Fields 6,  Emad Tajkhorshid 1 3 4 5,  Gee W Lau 9,  Paul J Hergenrother 10 11 12
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • 2 Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • 3 Theoretical and Computational Biophysics Group, NIH Center for Macromolecular Modeling and Visualization, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • 4 Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • 5 Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • 6 High-Performance Computing in Biology, Roy J. Carver Biotechnology Center, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • 7 Veterinary Diagnostic Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • 8 Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • 9 Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • 10 Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA. [email protected].
  • 11 Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA. [email protected].
  • 12 Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA. [email protected].
PMID: 38811738 DOI: 10.1038/s41586-024-07502-0
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.

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