title: PhoP-regulated Salmonella resistance to the antimicrobial peptides magainin 2 and polymyxin B.
abstract: In Salmonella enterica, the PhoP-PhoQ two-component system governs resistance to structurally different antimicrobial peptides including the alpha-helical magainin 2, the beta-sheet defensins and the cyclic lipopeptide polymyxin B. To identify the PhoP-regulated determinants mediating peptide resistance, we prepared a plasmid library from a phoP mutant, introduced it into a phoP mutant and selected for magainin-resistant clones. One of the clones harboured the PhoP-activated ugtL gene, deletion of which rendered Salmonella susceptible to magainin 2 and polymyxin B, but not defensin HNP-1. We established that ugtL encodes an inner membrane protein that promotes the formation of monophosphorylated lipid A in the lipopolysaccharide. Inactivation of both ugtL and the regulatory gene pmrA, which controls lipid A modifications required for resistance to polymxyin B (but not to magainin 2) and is post-transcriptionally activated by the PhoP-PhoQ system, resulted in a strain that was as susceptible to polymyxin B as a phoP mutant. The most frequently recovered clone harboured the yqjA gene, which we show is PhoP regulated and required for resistance to magainin 2 but not to polymyxin B or defensin HNP-1. Our results indicate that different PhoP-mediated modifications in lipid A are necessary for resistance to different antimicrobial peptides.
authors.affiliation: Department of Molecular Microbiology, Campus Box 8230, Washington University, St Louis, MO 63110, USA.
authors.forename: Yixin
authors.initials: Y
authors.lastname: Shi
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Cromie
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: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000502:physiology*; D024881:Drug Resistance, Bacterial / Q000502:physiology*; D015964:Gene Expression Regulation, Bacterial; D005798:Genes, Bacterial; D008826:Microbial Sensitivity Tests; D010455:Peptides / Q000494:pharmacology; D011113:Polymyxins / Q000494:pharmacology*; D012475:Salmonella / Q000187:drug effects* / Q000235:genetics; D015533:Transcriptional Activation
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D010455:Peptides; D011113:Polymyxins; C061064:PhoP protein, Bacteria