title: The PmrA-regulated pmrC gene mediates phosphoethanolamine modification of lipid A and polymyxin resistance in Salmonella enterica.
abstract: The PmrA/PmrB regulatory system of Salmonella enterica controls the modification of lipid A with aminoarabinose and phosphoethanolamine. The aminoarabinose modification is required for resistance to the antibiotic polymyxin B, as mutations of the PmrA-activated pbg operon or ugd gene result in strains that lack aminoarabinose in their lipid A molecules and are more susceptible to polymyxin B. Additional PmrA-regulated genes appear to participate in polymyxin B resistance, as pbgP and ugd mutants are not as sensitive to polymyxin B as a pmrA mutant. Moreover, the role that the phosphoethanolamine modification of lipid A plays in the resistance to polymyxin B has remained unknown. Here we address both of these questions by establishing that the PmrA-activated pmrC gene encodes an inner membrane protein that is required for the incorporation of phosphoethanolamine into lipid A and for polymyxin B resistance. The PmrC protein consists of an N-terminal region with five transmembrane domains followed by a large periplasmic region harboring the putative enzymatic domain. A pbgP pmrC double mutant resembled a pmrA mutant both in its lipid A profile and in its susceptibility to polymyxin B, indicating that the PmrA-dependent modification of lipid A with aminoarabinose and phosphoethanolamine is responsible for PmrA-regulated polymyxin B resistance.
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Hyunwoo
authors.initials: H
authors.lastname: Lee
authors.forename: Fong-Fu
authors.initials: FF
authors.lastname: Hsu
authors.forename: John
authors.initials: J
authors.lastname: Turk
authors.forename: Eduardo A
authors.initials: EA
authors.lastname: Groisman
mesh_terms: D001426:Bacterial Proteins / Q000502:physiology*; D024881:Drug Resistance, Bacterial; D004983:Ethanolamines / Q000378:metabolism*; D005290:Ferric Compounds / Q000494:pharmacology; D005798:Genes, Bacterial / Q000502:physiology*; D008050:Lipid A / Q000378:metabolism*; D011112:Polymyxin B / Q000494:pharmacology*; D019779:Salmonella enterica / Q000187:drug effects / Q000235:genetics* / Q000472:pathogenicity
chemical_list: D001426:Bacterial Proteins; D004983:Ethanolamines; D005290:Ferric Compounds; D008050:Lipid A; C081902:pmrA protein, Bacteria; C005448:phosphorylethanolamine; D011112:Polymyxin B