title: The MisR Response Regulator Is Necessary for Intrinsic Cationic Antimicrobial Peptide and Aminoglycoside Resistance in Neisseria gonorrhoeae.
abstract: During infection, the sexually transmitted pathogen Neisseria gonorrhoeae (the gonococcus) encounters numerous host-derived antimicrobials, including cationic antimicrobial peptides (CAMPs) produced by epithelial and phagocytic cells. CAMPs have both direct and indirect killing mechanisms and help link the innate and adaptive immune responses during infection. Gonococcal CAMP resistance is likely important for avoidance of host nonoxidative killing systems expressed by polymorphonuclear granulocytes (e.g., neutrophils) and intracellular survival. Previously studied gonococcal CAMP resistance mechanisms include modification of lipid A with phosphoethanolamine by LptA and export of CAMPs by the MtrCDE efflux pump. In the related pathogen Neisseria meningitidis, a two-component regulatory system (2CRS) termed MisR-MisS has been shown to contribute to the capacity of the meningococcus to resist CAMP killing. We report that the gonococcal MisR response regulator but not the MisS sensor kinase is involved in constitutive and inducible CAMP resistance and is also required for intrinsic low-level resistance to aminoglycosides. The 4- to 8-fold increased susceptibility of misR-deficient gonococci to CAMPs and aminoglycosides was independent of phosphoethanolamine decoration of lipid A and the levels of the MtrCDE efflux pump and seemed to correlate with a general increase in membrane permeability. Transcriptional profiling and biochemical studies confirmed that expression of lptA and mtrCDE was not impacted by the loss of MisR. However, several genes encoding proteins involved in membrane integrity and redox control gave evidence of being MisR regulated. We propose that MisR modulates the levels of gonococcal susceptibility to antimicrobials by influencing the expression of genes involved in determining membrane integrity.
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Justin L
authors.initials: JL
authors.lastname: Kandler
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Concerta L
authors.initials: CL
authors.lastname: Holley
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Reimche
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Vijaya
authors.initials: V
authors.lastname: Dhulipala
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Jacqueline T
authors.initials: JT
authors.lastname: Balthazar
authors.affiliation: Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia, USA.
authors.forename: Artur
authors.initials: A
authors.lastname: Muszyński
authors.affiliation: Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia, USA.
authors.forename: Russell W
authors.initials: RW
authors.lastname: Carlson
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA The Emory Antibiotic Resistance Center, Emory University School of Medicine, Atlanta, Georgia, USA Laboratories of Bacterial Pathogenesis, Veterans Affairs Medical Center, Decatur, Georgia, USA wshafer@emory.edu.
authors.forename: William M
authors.initials: WM
authors.lastname: Shafer
mesh_terms: D000617:Aminoglycosides / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism*; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D006069:Gonorrhea / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D008050:Lipid A / Q000378:metabolism; D009344:Neisseria gonorrhoeae / Q000187:drug effects / Q000378:metabolism*; D009345:Neisseria meningitidis / Q000187:drug effects / Q000378:metabolism
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D001426:Bacterial Proteins; D008050:Lipid A