We report the biochemical characterization of a set of important quorum sensing (QS) receptors in the presence of non-native ligands. Many common bacterial pathogens regulate virulent behaviors using QS, a form of intraspecies cell-to-cell communication. Gram-negative bacteria use N-acyl homoserine lactone (AHL) signals and intracellular LuxR-type proteins for QS. At high cell density, AHL:LuxR-type receptor binding modulates transcription of a range of genes involved in group behaviors. Interference of QS has attracted interest as an antivirulence target, and blocking AHL:LuxR-type receptor binding has been a central focus of many QS inhibition approaches. Synthetic antagonists have been identified for myriad LuxR-type receptors, albeit with modest potency. Despite extensive efforts, our understanding of how non-native ligands alter LuxR-type receptor activity remains limited due to the instability of receptors in the absence of their native ligand. SdiA and QscR, unlike most LuxR-type receptors, appear more stable in the absence of ligand; thus, we believe these receptors provide a unique opportunity to characterize the mechanisms by which small molecules interact with LuxR-type receptors. Through examination of in vitro receptor-ligand complex stability, dimerization, and DNA binding affinity, we have delineated the modes by which non-native agonists and antagonists alter receptor activity. This work lays the foundation for understanding the mechanisms of LuxR-type receptor inhibition, and a route toward the design of next-generation antagonists with improved potencies and efficacies.

Window into the black box of quorum sensing: New LuxR-type protein models for the investigation of ligand-receptor and receptor-DNA interactions in vitro

2019 Fall National Meeting

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