Quorum sensing is a process of bacterial communication that relies on the production, detection, and response to extracellular signaling molecules called autoinducers. Bacteria use quorum sensing to regulate behaviors that are only effective when carried out in unison by a population. Quorum-sensing-controlled processes include biofilm formation and the expression of virulence factors. The long-term goal of this research is to explore the molecular mechanisms that pathogenic bacteria use for quorum sensing, and to use this knowledge to design potent quorum-sensing antagonists with potential therapeutic uses. Here, I propose studies of LuxR-type quorum-sensing receptors from the pathogens Chromobacterium violaceum and Pseudomonas aeruginosa. To develop a molecular understanding of how quorum-sensing signals are detected, and how signal detection can be disrupted by small molecules, I will carry out studies that combine bacterial genetics, biochemistry, and high-throughput small molecule screening for quorum-sensing inhibitors. I will identify and characterize signaling antagonists and determine their mechanisms of action. These studies will provide lead compounds for the development of antibacterial drugs designed to modulate quorum sensing. More generally, these molecules will provide tools for studying intra- and inter-cellular signal transmission, cell- cell communication, self versus non-self recognition, and the evolution of collective behaviors. PUBLIC HEALTH RELEVANCE: The long-term goal of this research is to explore the molecular mechanisms that bacteria use for cell-cell communication, a process known as quorum sensing. Since numerous pathogenic bacteria use quorum sensing to transition into and out of disease-causing states, drugs that block quorum sensing may be valuable alternatives to traditional antibiotics. Accordingly, the aims of this research are to understand quorum-sensing mechanisms and to design potent quorum-sensing antagonists that target pathogenic bacteria and have potential therapeutic value.