The MisR Response Regulator Is Necessary for Intrinsic Cationic Antimicrobial Peptide and Aminoglycoside Resistance in Neisseria gonorrhoeae
| Autor: | Artur Muszyński, Justin L. Kandler, Russell W. Carlson, Jacqueline T. Balthazar, Concerta L. Holley, Vijaya Dhulipala, Jennifer L. Reimche, William M. Shafer |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Membrane permeability 030106 microbiology Drug resistance Biology Neisseria meningitidis medicine.disease_cause Microbiology Lipid A 03 medical and health sciences Gonorrhea Bacterial Proteins Mechanisms of Resistance Drug Resistance Bacterial medicine Humans Pharmacology (medical) Pathogen Pharmacology Neisseria gonorrhoeae Anti-Bacterial Agents Response regulator Infectious Diseases Aminoglycosides Efflux Antimicrobial Cationic Peptides |
| Zdroj: | Antimicrobial agents and chemotherapy. 60(8) |
| ISSN: | 1098-6596 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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