title: Cold Stress Makes Escherichia coli Susceptible to Glycopeptide Antibiotics by Altering Outer Membrane Integrity.
abstract: A poor understanding of the mechanisms by which antibiotics traverse the outer membrane remains a considerable obstacle to the development of novel Gram-negative antibiotics. Herein, we demonstrate that the Gram-negative bacterium Escherichia coli becomes susceptible to the narrow-spectrum antibiotic vancomycin during growth at low temperatures. Heterologous expression of an Enterococcus vanHBX vancomycin resistance cluster in E. coli confirmed that the mechanism of action was through inhibition of peptidoglycan biosynthesis. To understand the nature of vancomycin permeability, we screened for strains of E. coli that displayed resistance to vancomycin at low temperature. Surprisingly, we observed that mutations in outer membrane biosynthesis suppressed vancomycin activity. Subsequent chemical analysis of lipopolysaccharide from vancomycin-sensitive and -resistant strains confirmed that suppression was correlated with truncations in the core oligosaccharide of lipopolysaccharide. These unexpected observations challenge the current understanding of outer membrane permeability, and provide new chemical insights into the susceptibility of E. coli to glycopeptide antibiotics.
authors: Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8N 3Z5, Canada.
authors: Jonathan M
authors: JM
authors: Stokes
authors: Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8N 3Z5, Canada.
authors: Shawn
authors: S
authors: French
authors: Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON N1G 2W1, Canada.
authors: Olga G
authors: OG
authors: Ovchinnikova
authors: Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON N1G 2W1, Canada.
authors: Catrien
authors: C
authors: Bouwman
authors: Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON N1G 2W1, Canada.
authors: Chris
authors: C
authors: Whitfield
authors: Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8N 3Z5, Canada. Electronic address: ebrown@mcmaster.ca.
authors: Eric D
authors: ED
authors: Brown
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects; D003080:Cold Temperature; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D006020:Glycopeptides / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D014640:Vancomycin / Q000737:chemistry / Q000494:pharmacology*; D020713:Vancomycin Resistance / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D006020:Glycopeptides; D014640:Vancomycin