Role of EnvZ/OmpR Two‐component System in Antibiotic Resistance in Salmonella enterica Serovar Enteritidis

Abstract

Outer membrane porins (OMPs) form water‐filled open channels and allow the entry of small hydrophilic antibiotics. Thus, compositional modulation of OMPs is frequently observed in multidrug‐resistant bacteria, including a human pathogen Salmonella enterica. However, the mechanism by which S. entericamodulates OMP composition to enhance antibiotic resistance has not been well elucidated. In this study, we found that the S. enterica serovar Enteritidis strain with an active state of EnvZ/OmpR is highly resistant to various antibiotics, especially β‐lactams. Transcriptome analysis discovered that the active state of EnvZ/OmpR induces differential expression of multiple OMP genes, including SEN1522, SEN2875, ompD, and ompW. Biochemical analyses identified that OmpR activates SEN1522 and SEN2875 but represses ompD and ompW by directly binding to their upstream regions. Interestingly, the cellular level of OmpR determines the expression of the four OMP genes, and particularly, the phosphorylation of OmpR is not required for the repression of ompD and ompW. Phenotypic analysis revealed that a decreased expression of ompD is responsible for the EnvZ/OmpR‐mediated resistance to β‐lactams in S. Enteritidis. Notably, EnvZ/OmpR represses the expression of ompD upon exposure to β‐lactams and presumably provides S. Enteritidis with benefits for survival. Altogether, this study suggests that EnvZ/OmpR remodels OMP composition in response to β‐lactams and thereby enhances resistance in S. Enteritidis to the antibiotics.