title: A cell wall damage response mediated by a sensor kinase/response regulator pair enables beta-lactam tolerance.
abstract: The bacterial cell wall is critical for maintenance of cell shape and survival. Following exposure to antibiotics that target enzymes required for cell wall synthesis, bacteria typically lyse. Although several cell envelope stress response systems have been well described, there is little knowledge of systems that modulate cell wall synthesis in response to cell wall damage, particularly in Gram-negative bacteria. Here we describe WigK/WigR, a histidine kinase/response regulator pair that enables Vibrio cholerae, the cholera pathogen, to survive exposure to antibiotics targeting cell wall synthesis in vitro and during infection. Unlike wild-type V. cholerae, mutants lacking wigR fail to recover following exposure to cell-wall-acting antibiotics, and they exhibit a drastically increased cell diameter in the absence of such antibiotics. Conversely, overexpression of wigR leads to cell slimming. Overexpression of activated WigR also results in increased expression of the full set of cell wall synthesis genes and to elevated cell wall content. WigKR-dependent expression of cell wall synthesis genes is induced by various cell-wall-acting antibiotics as well as by overexpression of an endogenous cell wall hydrolase. Thus, WigKR appears to monitor cell wall integrity and to enhance the capacity for increased cell wall production in response to damage. Taken together, these findings implicate WigKR as a regulator of cell wall synthesis that controls cell wall homeostasis in response to antibiotics and likely during normal growth as well.
authors.affiliation: Howard Hughes Medical Institute, Brigham and Women's Hospital Division of Infectious Diseases and Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115;
authors.forename: Tobias
authors.initials: T
authors.lastname: Dörr
authors.affiliation: Laboratory for Molecular Infection Medicine Sweden, Department of Molecular Biology, Umeå Centre for Microbial Research, Umeå University, 90187 Umeå, Sweden.
authors.forename: Laura
authors.initials: L
authors.lastname: Alvarez
authors.affiliation: Howard Hughes Medical Institute, Brigham and Women's Hospital Division of Infectious Diseases and Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115;
authors.forename: Fernanda
authors.initials: F
authors.lastname: Delgado
authors.affiliation: Howard Hughes Medical Institute, Brigham and Women's Hospital Division of Infectious Diseases and Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115;
authors.forename: Brigid M
authors.initials: BM
authors.lastname: Davis
authors.affiliation: Laboratory for Molecular Infection Medicine Sweden, Department of Molecular Biology, Umeå Centre for Microbial Research, Umeå University, 90187 Umeå, Sweden.
authors.forename: Felipe
authors.initials: F
authors.lastname: Cava
authors.affiliation: Howard Hughes Medical Institute, Brigham and Women's Hospital Division of Infectious Diseases and Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; mwaldor@research.bwh.harvard.edu.
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Waldor
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000378:metabolism*; D002473:Cell Wall / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002876:Chromosomes, Bacterial / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D005798:Genes, Bacterial; D005816:Genetic Complementation Test; D056426:Genetic Loci; D000071677:Histidine Kinase; D006706:Homeostasis / Q000187:drug effects; D007501:Iron / Q000378:metabolism; D050296:Microbial Viability / Q000187:drug effects; D009068:Movement / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D010406:Penicillins / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D018085:Regulon / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects; D014734:Vibrio cholerae / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D047090:beta-Lactams / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D010406:Penicillins; D047090:beta-Lactams; D007501:Iron; D011494:Protein Kinases; D000071677:Histidine Kinase
keywords: antibiotic tolerance; cell envelope; peptidoglycan; stress response; two component system