Sep, a YieP homolog, orchestrates membrane remodeling and multi-stress resistance in Salmonella enterica isolates from food

Salmonella enterica is a major foodborne pathogen capable of withstanding multiple environmental stresses commonly encountered during food processing. However, the genetic mechanisms underlying its membrane stress adaptation remain incompletely understood. Here, we characterized sep, a previously unstudied GntR-family transcriptional regulator homologous to yieP in Escherichia coli, to evaluate its role in stress resistance and membrane remodeling in S. enterica. Deletion of sep did not affect growth under non-stress conditions but significantly impaired survival following exposure to heat (55 °C), desiccation (30 % RH), osmotic (10 % NaCl), and oxidative (5 % H₂O₂) stress. The Δsep mutant also exhibited reduced biofilm formation, lower antibiotic tolerance, compromised membrane integrity and potential, and altered fatty acid profiles, including loss of cyclopropane fatty acids and accumulation of unsaturated fatty acids. These phenotypes correlated with transcriptional downregulation of cfa (cyclopropane fatty acid synthase) and upregulation of envelope and oxidative stress response genes (rpoE, osmY, katG). Complementation with plasmid-borne sep restored all defects to near wild-type levels. Our findings reveal that Sep is a key regulator of membrane lipid remodeling and stress adaptation in S. enterica, with implications for the organism's persistence in food production environments. This study identifies sep as a potential molecular target for strategies aiming to reduce Salmonella resistance to thermal, oxidative, and desiccation-based control interventions in the food chain.