Salmonella stress response systems as targets for anti-virulence strategies

Due to the rapid development of antibiotic resistance, novel strategies to cope with bacterial infections are urgently required. Ideally, these strategies should exert less selection pressure for resistance than traditional antibiotics. One potential approach is to target the bacterial stress response systems. Bacteria use these regulatory stress response systems to detect and endure the harsh stresses inside and outside the host. Furthermore, these stress responses frequently influence the pathogens' virulence. Therefore, we explored the potential of alternative antimicrobial strategies that target stress response systems, focusing on the common enteropathogen Salmonella as a model system. We first elucidated the role of the major Salmonella stress responses in virulence and tolerance phenotypes. Hereto, we systematically characterized how the genomic deletion of each major stress response regulator impacts biofilm formation, antibiotic tolerance, persistence, mutation rate, epithelial adhesion, and cell invasion. We identified the general stress response (RpoS), the SOS response (RecA), and the exocytoplasmic stress response (RpoE) as key systems involved in multiple tolerance and virulence phenotypes. Subsequently, we evaluated whether known chemical inhibitors targeting these stress response systems could effectively reduce Salmonella virulence and tolerance. Specifically, we tested epigallocatechin gallate as an RpoS inhibitor, Batimastat as an inhibitor for RpoE, and BRITE-338,733 for RecA. While epigallocatechin gallate and Batimastat showed no significant effects under the tested conditions, BRITE-338,733 successfully disrupted the SOS response, reducing antibiotic tolerance in Salmonella. Our work underscores that bacterial stress response systems significantly contribute to virulence and tolerance and thus constitute promising targets to combat Salmonella infections.