EnvZ/OmpR two-component system induces antibiotic resistance in Salmonella enterica Serovar Enteritidis in response to ?-lactams

Abstract Outer membrane porins (OMPs) of Gram-negative bacteria including Salmonella entericaserovar Enteritidis allow the entry of small hydrophilic antibiotics. S. Enteritidis is a human pathogen causing food-borne illnesses, and infection by S.Enteritidis often results in severe invasive disease and requires antibiotic treatments. Although compositional modulation of OMPs is frequently observed in multidrug-resistant S.Enteritidis, little is known about the mechanisms by which the pathogen modulates OMP composition to enhance antibiotic resistance. Here, we found that the S.Enteritidis strain with an active state of EnvZ/OmpR two-component system is highly resistant to various antibiotics, especially β-lactams. Transcriptome analysis showed that the active state of EnvZ/OmpR induces differential expression of multiple OMP genes, including SEN1522, SEN2875, ompD, and ompW. Interestingly, the cellular level of response regulator OmpR determines the expression of the four OMP genes, and phosphorylation of OmpR is not necessary for the regulation of ompDand ompW. Phenotypic analysis revealed that ompDis a key OMP gene responsible for the EnvZ/OmpR-mediated antibiotic resistance in S.Enteritidis. Notably, EnvZ/OmpR responds to the presence of β-lactams and provides S.Enteritidis with direct benefits for survival. Altogether, this study suggests that EnvZ/OmpR remodels OMP composition of S.Enteritidis in response to β-lactams and enhances antibiotic resistance. This research was supported by Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Education (NRF-2022R1A6A3A01086815).