title: PhoQ mutations promote lipid A modification and polymyxin resistance of Pseudomonas aeruginosa found in colistin-treated cystic fibrosis patients.
abstract: Pseudomonas aeruginosa can develop resistance to polymyxin and other cationic antimicrobial peptides. Previous work has shown that mutations in the PmrAB and PhoPQ regulatory systems can confer low to moderate levels of polymyxin resistance (MICs of 8 to 64 mg/liter) in laboratory and clinical strains of this organism. To explore the role of PhoPQ in high-level clinical polymyxin resistance, P. aeruginosa strains with colistin MICs > 512 mg/liter that had been isolated from cystic fibrosis patients treated with inhaled colistin (polymyxin E) were analyzed. Probable loss-of-function phoQ alleles found in these cystic fibrosis strains conferred resistance to polymyxin. Partial and complete suppressor mutations in phoP were identified in some cystic fibrosis strains with resistance-conferring phoQ mutations, suggesting that additional loci can be involved in polymyxin resistance in P. aeruginosa. Disruption of chromosomal phoQ in the presence of an intact phoP allele stimulated 4-amino-l-arabinose addition to lipid A and induced transcription from the promoter of the pmrH (arnB) operon, consistent with the known role of this lipid A modification in polymyxin resistance. These results indicate that phoQ loss-of-function mutations can contribute to high-level polymyxin resistance in clinical strains of P. aeruginosa.
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, Washington 02114, USA.
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Miller
authors.forename: Mark K
authors.initials: MK
authors.lastname: Brannon
authors.forename: Laurel
authors.initials: L
authors.lastname: Stevens
authors.forename: Helle Krogh
authors.initials: HK
authors.lastname: Johansen
authors.forename: Sara E
authors.initials: SE
authors.lastname: Selgrade
authors.forename: Samuel I
authors.initials: SI
authors.lastname: Miller
authors.forename: Niels
authors.initials: N
authors.lastname: Høiby
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Moskowitz
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000235:genetics*; D003091:Colistin / Q000494:pharmacology / Q000627:therapeutic use; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000382:microbiology; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D005260:Female; D006801:Humans; D008050:Lipid A / Q000737:chemistry; D008297:Male; D008826:Microbial Sensitivity Tests; D009154:Mutation; D011113:Polymyxins / Q000494:pharmacology* / Q000627:therapeutic use; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D008050:Lipid A; C079792:PhoQ protein, Bacteria; D011113:Polymyxins; D003091:Colistin