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

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 enzyme-coupled high-throughput cell-free screen to...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2013-08, Vol.110 (34), p.13815-13820
Main Authors: Christensen, Quin H., Grove, Tyler L., Booker, Squire J., Greenberg, E. Peter
Format: Article
Language:English
Subjects:
Acyl-Butyrolactones - metabolism
Antibiotics
Biochemistry
Biological Sciences
Biosynthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - isolation & purification
Enzymes
Escherichia coli
Fluorescence
Gene Expression Regulation, Bacterial - physiology
Gram-negative bacteria
High-Throughput Screening Assays
Indoles
Inhibitory Concentration 50
Kinetics
Lactones
Ligases - antagonists & inhibitors
Ligases - metabolism
Medical treatment
Molecular Structure
Oxazines
Proteobacteria - physiology
Pseudomonas aeruginosa
Quorum sensing
Quorum Sensing - physiology
Receptors
Signal transduction
Velocity
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Summary: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 enzyme-coupled 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 K ᵢ 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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1313098110