Ithaca College

Biochemistry students Colleen O'Loughlin and Raleene Gatmaitan and chemistry department chair Scott Ulrich coauthored a paper in the Molecular Cell journal.

The paper is titled "A Quorum Sensing Antagonist That Targets Both Membrane-Bound and Cytoplasmic Receptors Controls Bacterial Pathogenicity."

In addition to O'Loughlin, Gatmaitan, and Ulirch, the paper's other coauthors were Lee Swem, Danielle Swem, and Bonnie Bassler of Princeton University. The article has just been accepted and will appear in print and online shortly.

Abstract

Quorum sensing is a process of bacterial cell-cell communication that involves production and detection of secreted signal molecules called autoinducers. Gram-negative bacteria use acyl-homoserine lactones (AHLs) as autoinducers which are detected by one of two receptor types. First, cytoplasmic LuxR-type receptors bind accumulated intracellular AHLs and the AHL-LuxR complexes bind DNA and alter gene expression. Second, membrane-bound LuxN-type histidine kinase receptors bind accumulated extracellular AHLs. The AHL-LuxN complexes relay information internally by phosphorylation cascades that impinge on downstream DNA binding proteins that direct changes in gene expression. Here we describe that a small molecule scaffold, previously identified as an antagonist of LuxN-type receptors, is also a potent antagonist of the LuxR family, despite the differences in receptor structure, localization, AHL specificity and mechanism of signaling. We also describe the key biochemical differences between the antagonized and agonized form of the LuxR family receptor. A focused library of derivatives of the original antagonist was synthesized and optimized for potency. Remarkably, the most potent antagonist protects the model eukaryote Caenorhabditis elegans from the bacterial pathogen Chromobacterium violaceum,  validating the idea that quorum sensing inhibitors have potential clinical use as novel antimicrobials.