A high-throughput screen for quorum-sensing inhibitors that target acyl-homoserine lactone synthases

Quin H. Christensen, Tyler L. Grove, Squire J. Booker, E. Peter Greenberg

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

Many Proteobacteria use N-acyl-homoserine lactone (acyl-HSL) quorum sensing to control specific genes. Acyl-HSL synthesis requires unique enzymes that use S-adenosyl methionine as an acyl acceptor and amino acid donor. We developed and executed an enzymecoupled high-throughput cell-free screen to discover acyl-HSL synthase inhibitors. The three strongest inhibitors were equally active against two different acyl-HSL synthases: Burkholderia mallei BmaI1 and Yersinia pestis YspI. Two of these inhibitors showed activity in whole cells. The most potent compound behaves as a noncompetitive inhibitor with a Ki of 0.7 μM and showed activity in a cell-based assay. Quorum-sensing signal synthesis inhibitors will be useful in attempts to understand acyl-HSL synthase catalysis and as a tool in studies of quorum-sensing control of gene expression. Because acyl- HSL quorum-sensing controls virulence of some bacterial pathogens, anti-quorum-sensing chemicals have been sought as potential therapeutic agents. Our screen and identification of acyl-HSL synthase inhibitors serve as a basis for efforts to target quorum-sensing signal synthesis as an antivirulence approach.

Original languageEnglish (US)
Pages (from-to)13815-13820
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number34
DOIs
StatePublished - Aug 28 2013

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