Anti-virulence approaches that target infectivity rather than growth may be less prone to resistance development, and thus, serve as attractive antimicrobial strategies. Quorum sensing (QS) systems control virulence in a variety of bacterial pathogens through chemical-mediated, cell-cell communication circuits. In the most common QS system in Gram-negative bacteria, a LuxI-type synthase produces an N-acyl L-homoserine-lactone (AHL) signal that is sensed by a LuxR-type receptor at high population density to coordinate group behavior. These receptors have proven difficult to characterize in vitro because of their poor stability without their native signal; however, the LuxR-type receptor found in E. coli, SdiA, appears to be uniquely well behaved in vitro. Interestingly, SdiA lacks a cognate LuxI-type synthase, and regulates QS-related gene expression in response to signals produced by other bacteria in the E. coli environment. Many questions remain about the mechanism by which LuxR-type receptors function, and the role of SdiA in disease is unclear. Chemical modulators of SdiA could provide a new strategy to study the E. coli QS system, and due to the intrinsic stability of SdiA, could be used in biophysical studies to provide insights into the mechanisms by which LuxR-type receptors operate in general. In this presentation, we outline our recent investigations into the activity profiles of a library of approximately 150 non-native AHLs using a cell-based gene reporter of SdiA activity. These studies revealed a collection of potent agonists and antagonists of QS in E. coli, and our lead compounds were capable of blocking QS phenotypes in E. coli as measured by an acid resistance assay. These compounds represent some of the first chemical tools to study SdiA in E. coli and provide a pathway to new biophysical experiments to illuminate AHL:LuxR-receptor interactions.

Development of chemical tools to probe quorum sensing in Escherichia coli

2019 Spring National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.