A quorum-sensing antagonist targets both membrane-bound and cytoplasmic receptors and controls bacterial pathogenicity.

TitleA quorum-sensing antagonist targets both membrane-bound and cytoplasmic receptors and controls bacterial pathogenicity.
Publication TypeJournal Article
Year of Publication2009
AuthorsSwem, LR, Swem, DL, O'Loughlin, CT, Gatmaitan, R, Zhao, B, Ulrich, SM, Bassler, BL
JournalMol Cell
Volume35
Issue2
Pagination143-53
Date Published2009 Jul 31
ISSN1097-4164
KeywordsAnimals, Anti-Bacterial Agents, Bacterial Proteins, Caenorhabditis elegans, Chromobacterium, Escherichia coli, Inhibitory Concentration 50, Microbial Sensitivity Tests, Quorum Sensing, Receptors, Cell Surface, Receptors, Cytoplasmic and Nuclear, Repressor Proteins, Trans-Activators
Abstract

<p>Quorum sensing is a process of bacterial communication involving production and detection of secreted molecules called autoinducers. Gram-negative bacteria use acyl-homoserine lactone (AHL) autoinducers, which are detected by one of two receptor types. First, cytoplasmic LuxR-type receptors bind accumulated intracellular AHLs. AHL-LuxR complexes bind DNA and alter gene expression. Second, membrane-bound LuxN-type receptors bind accumulated extracellular AHLs. AHL-LuxN complexes relay information internally by phosphorylation cascades that direct gene expression changes. Here, we show that a small molecule, previously identified as an antagonist of LuxN-type receptors, is also a potent antagonist of the LuxR family, despite differences in receptor structure, localization, AHL specificity, and signaling mechanism. Derivatives were synthesized and optimized for potency, and in each case, we characterized the mode of action of antagonism. The most potent antagonist protects Caenorhabditis elegans from quorum-sensing-mediated killing by Chromobacterium violaceum, validating the notion that targeting quorum sensing has potential for antimicrobial drug development.</p>

DOI10.1016/j.molcel.2009.05.029
Alternate JournalMol. Cell
PubMed ID19647512
PubMed Central IDPMC2741501
Grant List5R01 AI 054442 / AI / NIAID NIH HHS / United States
5R01GM065859 / GM / NIGMS NIH HHS / United States
GM787552 / GM / NIGMS NIH HHS / United States
N01-CO-12400 / CO / NCI NIH HHS / United States
R01 AI054442 / AI / NIAID NIH HHS / United States
R01 GM065859 / GM / NIGMS NIH HHS / United States
R01 GM065859-05A1 / GM / NIGMS NIH HHS / United States
R01 GM065859-06 / GM / NIGMS NIH HHS / United States
T32 GM007205 / GM / NIGMS NIH HHS / United States
/ / Howard Hughes Medical Institute / United States