Identification of the lipopolysaccharide modifications controlled by the Salmonella PmrA/PmrB system mediating resistance to Fe(III) and Al(III).
Iron is an essential metal but can be toxic in excess. While several homeostatic mechanisms prevent oxygen-dependent killing promoted by Fe(II), little is known about how cells cope with Fe(III), which kills by oxygen-independent means. Several Gram-negative bacterial species harbour a regulatory system - termed PmrA/PmrB - that is activated by and required for resistance to Fe(III). We now report the identification of the PmrA-regulated determinants mediating resistance to Fe(III) and Al(III) in Salmonella enterica serovar Typhimurium. We establish that these determinants remodel two regions of the lipopolysaccharide, decreasing the negative charge of this major constituent of the outer membrane. Remodelling entails the covalent modification of the two phosphates in the lipid A region with phosphoethanolamine and 4-aminoarabinose, which has been previously implicated in resistance to polymyxin B, as well as dephosphorylation of the Hep(II) phosphate in the core region by the PmrG protein. A mutant lacking the PmrA-regulated Fe(III) resistance genes bound more Fe(III) than the wild-type strain and was defective for survival in soil, suggesting that these PmrA-regulated lipopolysaccharide modifications aid Salmonella's survival and spread in non-host environments.
Nishino
Kunihiko
K
Department of Molecular Microbiology, Howard Hughes Medical Institute, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Hsu
Fong-Fu
FF
Turk
John
J
Cromie
Michael J
MJ
Wösten
Marc M S M
MM
Groisman
Eduardo A
EA
D000535:Aluminum / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D007501:Iron / Q000378:metabolism / Q000494:pharmacology*; D008050:Lipid A / Q000378:metabolism; D008070:Lipopolysaccharides; D008969:Molecular Sequence Data; D009154:Mutation; D019897:Periplasm / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011112:Polymyxin B / Q000494:pharmacology; D012486:Salmonella typhimurium / Q000235:genetics / Q000378:metabolism*; D012988:Soil Microbiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D008050:Lipid A; D008070:Lipopolysaccharides; C500797:PbgP protein, Yersinia pestis; C409039:PmrB protein, bacteria; C510752:PmrC protein, E coli; D014157:Transcription Factors; C500798:Ugd protein, Yersinia pestis; C081902:pmrA protein, Bacteria; D000535:Aluminum; D007501:Iron; D010744:Phosphoric Monoester Hydrolases; D011112:Polymyxin B