A Chemical Biology Approach to Interrogate Quorum-Sensing Regulated Behaviors at the Molecular and Cellular Level

• Known quorum-sensing proteins were downregulated specifically in response to a QS antagonist
• Developed an approach to map QS networks without reliance on genetic manipulation
• No observation of clear link between QS signaling and virulence in S. typhimurium
• Demonstrates need to examine QS networks at genomic, proteomic, and phenotypic levels

SummarySmall molecule probes have been used extensively to explore biologic systems and elucidate cellular signaling pathways. In this study, we use an inhibitor of bacterial communication to monitor changes in the proteome of Salmonella enterica serovar Typhimurium with the aim of discovering unrecognized processes regulated by AI-2-based quorum-sensing (QS), a mechanism of bacterial intercellular communication that allows for the coordination of gene expression in a cell density-dependent manner. In S. typhimurium, this system regulates the uptake and catabolism of intercellular signals and has been implicated in pathogenesis, including the invasion of host epithelial cells. We demonstrate that our QS antagonist is capable of selectively inhibiting the expression of known QS-regulated proteins in S. typhimurium, thus attesting that QS inhibitors may be used to confirm proposed and elucidate previously unidentified QS pathways without relying on genetic manipulation.