PMRA-PMRB-REGULATED GENES NECESSARY FOR 4-AMINOARABINOSE LIPID-A MODIFICATION AND POLYMYXIN RESISTANCE

Antimicrobial peptides are distributed throughout the animal kingdom a nd are a key component of innate immunity. Salmonella typhimurium regu lates mechanisms of resistance to cationic antimicrobial peptides thro ugh the two-component systems PhoP-PhoQ and PmrA-PmrB. Polymyxin resis tance is encoded by the PmrA-PmrB regulon, whose products modify the l ipopolysaccharide (LPS) core and lipid A regions with ethanolamine and add aminoarabinose to the 4' phosphate of lipid A. Two PmrA-PmrB-regu lated S. typhimurium loci (pmrE and pmrF) have been identified that ar e necessary for resistance to polymyxin and for the addition of aminoa rabinose to lipid A. One locus, pmrE, contains a single gene previousl y identified as pagA (or ugd) that is predicted to encode a UDP-glucos e dehydrogenase. The second locus, pmrF, is the second gene of a putat ive operon predicted to encode seven proteins, some with similarity to glycosyltransferases and other complex carbohydrate biosynthetic enzy mes. Genes immediately flanking this putative operon are also regulate d by PmrA-PmrB and/or have been associated with S. typhimurium polymyx in resistance. This work represents the first identification of non-re gulatory genes necessary for modification of lipid A and subsequent an timicrobial peptide resistance, and provides support for the hypothesi s that lipid A aminoarabinose modification promotes resistance to cati onic antimicrobial peptides.