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

作者：Christensen Quin H; Grove Tyler L; Booker Squire J; Greenberg E Peter^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2013, 110(34): 13815-13820.

DOI：10.1073/pnas.1313098110

• bacterial communication
• cell-cell signaling
• enzyme inhibitors

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 mu M 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.

• 出版日期2013-8-20