PhoP‐regulated Salmonella resistance to the antimicrobial peptides magainin 2 and polymyxin B

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Abstract
In Salmonella enterica, the PhoP–PhoQ two‐component system governs resistance to structurally different antimicrobial peptides including the alpha‐helical magainin 2, the β‐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.