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A Gram-negative-selective antibiotic that spares the gut microbiome.
Muñoz, 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.
Afiliación
  • Muñoz KA; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • Ulrich RJ; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • Vasan AK; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • Sinclair M; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • Wen PC; 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.
  • Holmes JR; Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • Lee HY; Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • Hung CC; 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.
  • Fields CJ; Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • Tajkhorshid E; 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.
  • Lau GW; Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • Hergenrother PJ; Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Nature ; 630(8016): 429-436, 2024 Jun.
Article en En | MEDLINE | ID: mdl-38811738
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Simbiosis / Infecciones por Bacterias Gramnegativas / Descubrimiento de Drogas / Microbioma Gastrointestinal / Bacterias Gramnegativas / Antibacterianos Límite: Animals / Female / Humans / Male Idioma: En Revista: Nature Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Simbiosis / Infecciones por Bacterias Gramnegativas / Descubrimiento de Drogas / Microbioma Gastrointestinal / Bacterias Gramnegativas / Antibacterianos Límite: Animals / Female / Humans / Male Idioma: En Revista: Nature Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido