title: PmrA-PmrB-regulated genes necessary for 4-aminoarabinose lipid A modification and polymyxin resistance.
abstract: Antimicrobial peptides are distributed throughout the animal kingdom and are a key component of innate immunity. Salmonella typhimurium regulates mechanisms of resistance to cationic antimicrobial peptides through the two-component systems PhoP-PhoQ and PmrA-PmrB. Polymyxin resistance is encoded by the PmrA-PmrB regulon, whose products modify the lipopolysaccharide (LPS) core and lipid A regions with ethanolamine and add aminoarabinose to the 4' phosphate of lipid A. Two PmrA-PmrB-regulated S. typhimurium loci (pmrE and pmrF) have been identified that are necessary for resistance to polymyxin and for the addition of aminoarabinose to lipid A. One locus, pmrE, contains a single gene previously identified as pagA (or ugd) that is predicted to encode a UDP-glucose dehydrogenase. The second locus, pmrF, is the second gene of a putative operon predicted to encode seven proteins, some with similarity to glycosyltransferases and other complex carbohydrate biosynthetic enzymes. Genes immediately flanking this putative operon are also regulated by PmrA-PmrB and/or have been associated with S. typhimurium polymyxin resistance. This work represents the first identification of non-regulatory genes necessary for modification of lipid A and subsequent antimicrobial peptide resistance, and provides support for the hypothesis that lipid A aminoarabinose modification promotes resistance to cationic antimicrobial peptides.
authors.affiliation: University of Washington, Department of Medicine, Seattle 98195, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Gunn
authors.forename: K B
authors.initials: KB
authors.lastname: Lim
authors.forename: J
authors.initials: J
authors.lastname: Krueger
authors.forename: K
authors.initials: K
authors.lastname: Kim
authors.forename: L
authors.initials: L
authors.lastname: Guo
authors.forename: M
authors.initials: M
authors.lastname: Hackett
authors.forename: S I
authors.initials: SI
authors.lastname: Miller
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001089:Arabinose / Q000031:analogs & derivatives* / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics* / Q000502:physiology; D003001:Cloning, Molecular; D004352:Drug Resistance, Microbial / Q000235:genetics*; D005798:Genes, Bacterial / Q000235:genetics; D017930:Genes, Reporter / Q000235:genetics; D008050:Lipid A / Q000737:chemistry*; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000235:genetics; D009876:Operon / Q000235:genetics; D011113:Polymyxins / Q000494:pharmacology*; D012486:Salmonella typhimurium / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014533:Uridine Diphosphate Glucose Dehydrogenase / Q000502:physiology
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D008050:Lipid A; C079792:PhoQ protein, Bacteria; D011113:Polymyxins; C016982:aminoarabinose; C081902:pmrA protein, Bacteria; C061064:PhoP protein, Bacteria; D001089:Arabinose; D014533:Uridine Diphosphate Glucose Dehydrogenase