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Polymyxin is the “last resort” of antibiotics. The self-induced resistance to polymyxin in Gram-negative bacteria could be mediated by lipopolysaccharide (LPS) modification, which is regulated by the two-component system, PhoP/PhoQ.  Yersinia enterocolitica  is a common foodborne pathogen. However, PhoP/PhoQ has not been thoroughly studied in  Y. enterocolitica . In this study, the functions of PhoP/PhoQ in  Y. enterocolitica  intrinsic resistance were investigated. The resistance of  Y. enterocolitica  was found to decrease with the deletion of PhoP/PhoQ. Further, PhoP/PhoQ was found to play an important role in maintaining membrane permeability, intercellular metabolism, and reducing membrane depolarization. Based on subsequent studies, the binding ability of polymyxin to  Y. enterocolitica  was decreased by the modification of LPS with structures, such as L-Ara4N and palmitate. Analysis of the gene transcription levels revealed that the LPS modification genes,  pagP  and  arn  operon, were downregulated with the deletion of PhoP/PhoQ in  Y. enterocolitica  during exposure to polymyxin. In addition,  pmrA ,  pmrB , and  eptA  were downregulated in the mutants compared with the wild-type strain. Such findings demonstrate that PhoP/PhoQ contributes to the intrinsic resistance of  Y. enterocolitica  toward polymyxins. LPS modification with L-Ara4N or palmitate is mainly responsible for the resistance of  Y. enterocolitica  to polymyxins. The transcription of genes related to LPS modification and PmrA/PmrB can be both affected by PhoP/PhoQ in  Y. enterocolitica . This study adds to current knowledge regarding the role of PhoP/PhoQ in intrinsic resistance of  Y. enterocolitica  to polymyxin.

The Role of the Two-Component System PhoP/PhoQ in Intrinsic Resistance of Yersinia enterocolitica to Polymyxin