Lu Cenbin, Kirsch Benjamin, Zimmer Christina, de Jong Johannes C, Henn Claudia, Maurer Christine K, Müsken Mathias, Häussler Susanne, Steinbach Anke, Hartmann Rolf W
Helmholtz Institute for Pharmaceutical Research Saarland, Campus C2.3, 66123 Saarbrücken, Germany.
Chem Biol. 2012 Mar 23;19(3):381-90. doi: 10.1016/j.chembiol.2012.01.015.
The pqs quorum sensing communication system of Pseudomonas aeruginosa controls virulence factor production and is involved in biofilm formation, therefore playing an important role for pathogenicity. In order to attenuate P. aeruginosa pathogenicity, we followed a ligand-based drug design approach and synthesized a series of compounds targeting PqsR, the receptor of the pqs system. In vitro evaluation using a reporter gene assay in Escherichia coli led to the discovery of the first competitive PqsR antagonists, which are highly potent (K(d,app) of compound 20: 7 nM). These antagonists are able to reduce the production of the virulence factor pyocyanin in P. aeruginosa. Our finding offers insights into the ligand-receptor interaction of PqsR and provides a promising starting point for further drug design.
铜绿假单胞菌的群体感应通讯系统（pqs）控制着毒力因子的产生，并参与生物膜形成，因此在致病性方面发挥着重要作用。为了减弱铜绿假单胞菌的致病性，我们采用了基于配体的药物设计方法，合成了一系列靶向pqs系统受体PqsR的化合物。在大肠杆菌中使用报告基因检测进行的体外评估导致发现了首批竞争性PqsR拮抗剂，它们具有很高的活性（化合物20的K(d,app)：7 nM）。这些拮抗剂能够减少铜绿假单胞菌中毒力因子绿脓菌素的产生。我们的发现为PqsR的配体-受体相互作用提供了见解，并为进一步的药物设计提供了一个有希望的起点。
