title: Adaptive resistance to the "last hope" antibiotics polymyxin B and colistin in Pseudomonas aeruginosa is mediated by the novel two-component regulatory system ParR-ParS.
abstract: As multidrug resistance increases alarmingly, polymyxin B and colistin are increasingly being used in the clinic to treat serious Pseudomonas aeruginosa infections. In this opportunistic pathogen, subinhibitory levels of polymyxins and certain antimicrobial peptides induce resistance toward higher, otherwise lethal, levels of these antimicrobial agents. It is known that the modification of lipid A of lipopolysaccharide (LPS) is a key component of this adaptive peptide resistance, but to date, the regulatory mechanism underlying peptide regulation in P. aeruginosa has remained elusive. The PhoP-PhoQ and PmrA-PmrB two-component systems, which control this modification under low-Mg2+ conditions, do not appear to play a major role in peptide-mediated adaptive resistance, unlike in Salmonella where PhoQ is a peptide sensor. Here we describe the identification and characterization of a novel P. aeruginosa two-component regulator affecting polymyxin-adaptive resistance, ParR-ParS (PA1799-PA1798). This system was required for activation of the arnBCADTEF LPS modification operon in the presence of subinhibitory concentrations of polymyxin, colistin, or the bovine peptide indolicidin, leading to increased resistance to various polycationic antibiotics, including aminoglycosides. This study highlights the complexity of the regulatory network controlling resistance to cationic antibiotics and host peptides in P. aeruginosa, which has major relevance in the development and deployment of cationic antimicrobials.
authors.affiliation: Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, 232-2259 Lower Mall Research Station, Vancouver, BC, Canada V6T 1Z4.
authors.forename: Lucía
authors.initials: L
authors.lastname: Fernández
authors.forename: W James
authors.initials: WJ
authors.lastname: Gooderham
authors.forename: Manjeet
authors.initials: M
authors.lastname: Bains
authors.forename: Joseph B
authors.initials: JB
authors.lastname: McPhee
authors.forename: Irith
authors.initials: I
authors.lastname: Wiegand
authors.forename: Robert E W
authors.initials: RE
authors.lastname: Hancock
mesh_terms: D000222:Adaptation, Physiological; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D003091:Colistin / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation; D011112:Polymyxin B / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; C086169:ParR protein, bacteria; D012097:Repressor Proteins; D011112:Polymyxin B; D003091:Colistin