Many pathogenic bacteria regulate their phenotypes using a communication system called quorum sensing, which allows them to initiate virulence at high cell densities. Quorum sensing modulation via small molecule agonists or antagonists has been proposed as a strategy to prevent pathogenic behaviors. In Gram-negative bacteria, these communication pathways are orchestrated through the binding of native ligands—synthesized by the organisms—to transcription factors called LuxR-type receptors. In <i>Pseudomonas aeruginosa</i>, a full molecular understanding of ligand binding to the LasR receptor is lacking. To address this, we studied a non-native scaffold that was discovered in a high-throughput screen. After optimizing a synthetic approach toward this compound type, we screened compound libraries in whole cell and biochemical assays to better understand their structure activity relationships. Next, agonists of varying potency were cocrystallized with LasR, and the structures obtained deviated from those previously solved.  We propose a functional role to these structural differences that relates to ligand exchangeability, receptor stabilization, and signal transduction.

Design, synthesis, characterization, and structural studies of modulators of bacterial cell-to-cell signaling illuminate a secondary conformation of the <i>Pseudomonas aeruginosa </i>receptor LasR

2019 Spring National Meeting

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Design, synthesis, characterization, and structural studies of modulators of bacterial cell-to-cell signaling illuminate a secondary conformation of the Pseudomonas aeruginosa receptor LasR