以PqsR为靶点筛选铜绿假单胞菌群体感应调控抑制剂及联合用药研究

Pseudomonas aeruginosa (Pa) is an opportunistic pathogen that causes life-threatening nosocomial infections and is very difficult to treat. Especially in recent years, multidrug resistant and pan-drug resistant strains of Pa bring great difficulties in the clinical treatment. The virulence of Pa is controlled by a set of extracellular molecules regulation, known as the Quorum sensing (QS). The QS system regulates the production of virulence factor and without effect on bacterial growth can reduce natural selection pressure and therefore delay or avoid the development of resistance. Accordingly it has been recognized as a target for new anti-Pa therapies. Our preliminary studies show that the Pseudomonas quinolone signal is a crucial component of the complex quorum-sensing network of Pa and regulates the production of virulence factors. Transcription regulator PqsR (Receptor of the pqs system), an essential element of the pqs system activates the transcription of the pqs operon and downstream virulence factor production. Until now, researches focus on design new QS inhibitors which are analogues of the natural Pseudomonas quinolone signal molecular are limited by the lack of enough candidates and scaffolds. Moreover, bacteria have already developed mechanism to utilize some of the synthetic QS inhibitors to be agonists but not antagonist against QS of Pa according to the original design. So, our strategy is to set up a high throughput screening method based on pqs gene reporting system which is connected the critical receptor of the pqs system, PqsR. We hope to find new potential QS inhibitors from large compound libraries and to further clarify the mechanism of them. We also plan to further evaluate their activities not only the candidates themselves but also in combination with commercial antibiotics both in vitro and in vivo. More interestingly, by introducing dendrimer as the carrier of QS inhibitor and antibiotics, we hope to further assess their combination as a macromolecular complex together. All above is to support that PqsR is a new therapeutic targets for anti-Pa virulence and conducive to the settlement of Pa resistance problem and prevention.

铜绿假单胞菌 (Pseudomonas aeruginosa, Pa)是医院感染最常见的条件致病菌之一，其多药耐药和泛耐药株，更给临床治疗带来极大困难。细菌群体感应(Quorum sensing, QS)对Pa的致病力至关重要，干扰QS调控能有效降低毒性因子的产生，不易产生选择性压力和耐药突变，是治疗的新突破口。研究发现：喹诺酮信号分子通过与效应蛋白PqsR(Receptor of the pqs system, PqsR)结合，控制多种致病因子的转录和表达。计算机辅助设计信号分子类似物作为QS抑制剂具有局限性，我们拟建立以基因报告系统为基础的高通量筛选模型，从化合物库中筛选QS抑制剂；并研究与抗生素的联合使用；利用高分子材料Dendrimer作为载体，研究QS抑制剂与抗生素高分子复合物的成药性。为PqsR作为新的抗Pa药物筛选靶点提供理论基础和实验依据，有利于Pa耐药问题的解决和防治。