PmrA–PmrB‐regulated genes necessary for 4‐aminoarabinose lipid A modification and polymyxin resistance

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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.