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Summary

The PhoPQ two-component system of the intracellular pathogen Salmonella enterica senses and controls resistance to α-helical antimicrobial peptides (AMPs) by regulating covalent modifications of lipid A. A homologue of the phoPQ operon was found in the genome of the murine enteric extracellular pathogen, Citrobacter rodentium. Here we report that C. rodentium PhoPQ was apparently unable to mediate activation of target genes in the presence of α-helical AMPs. However, these AMPs activated C. rodentium PhoPQ expressed in a S. entericaΔphoPQ mutant. Analysis of the outer membrane (OM) fractions of the C. rodentium wild-type and ΔphoPQ strains led to the identification of an omptin family protease (CroP) that was absent in ΔphoPQ. Deletion of croP in C. rodentium resulted in higher susceptibility to α-helical AMPs, indicating a direct role of CroP in AMP resistance. CroP greatly contributed to the protection of the OM from AMP damage by actively degrading α-helical AMPs before they reach the periplasmic space. Accordingly, transcriptional activation of PhoP-regulated genes by α-helical AMPs was restored in the ΔcroP mutant. This study shows that resistance to α-helical AMPs by the extracellular pathogen C. rodentium relies primarily on the CroP OM protease.