Studies on the Pseudomonas aeruginosa Cell-to-Cell Signal PQS

描述(申请人提供)：铜绿假单胞菌是一种机会性病原体，是囊性纤维化患者医院感染和肺部感染的主要原因。这种无处不在的细菌在许多方面都能适应周围环境，其中之一就是利用小的化合物作为细胞间通讯的信号。这些信号控制着许多细胞功能，在感染过程中非常重要。这项建议将重点放在喹诺酮类信号系统上，该系统利用假单胞菌的喹诺酮信号(PQS；2-庚基-3-羟基-4-喹诺酮)作为转录调节因子PqsR的共同诱导剂。PqsR-PQS积极调节喹诺酮类药物的产生和感染所需的众多毒力因子。在感染的CF患者的肺中也会产生PQS，这意味着喹诺酮类信号在人类疾病中发挥了作用。在这项提议的头四年中，我们的进展导致了PQS合成途径的部分表征，并为我们提供了关于PQS的调节和合成以及PQS发挥的活性的信息。总体而言，现有的数据表明，PQS信号是铜绿假单胞菌细胞间通讯的一个复杂而重要的部分。正因为如此，我们提出的实验将有助于更好地理解PQS及其在细胞间信号传递中的作用。我们计划识别受PqsR-PQS调控的基因，并了解PqsR是如何控制的。我们的研究还将包括PqsE的功能分析，PqsE是PQS活动所需的效应器。我们计划继续对合成PQS所需的酶进行表征，以完成整个代谢途径的绘制。最后，我们将确定抑制PQS合成酶的化合物，并在铜绿假单胞菌感染的斑马鱼模型中测试这些化合物抑制毒力的能力。这些研究的完成将进一步加深我们对喹诺酮类药物信号的理解，并为今后旨在开发新的铜绿假单胞菌治疗方法的研究提供坚实的基础。

DESCRIPTION (provided by applicant): Pseudomonas aeruginosa is an opportunistic pathogen that is a leading cause of nosocomial infections and lung infections in individuals with cystic fibrosis (CF). This ubiquitous bacterium adapts to its surroundings in many ways, one of which is to utilize small chemical compounds as signals for cell-to-cell communication. These signals control many cellular functions and are important in the infectious process. This proposal will focus on the quinolone signaling system, which utilizes the Pseudomonas Quinolone Signal (PQS; 2-heptyl-3-hydroxy- 4-quinolone) as a coinducer for the transcriptional regulator PqsR. PqsR-PQS positively regulates quinolone production and numerous virulence factors required for infection. PQS is also produced in the lungs of infected CF patients, implying that quinolone signaling has a role in human disease. Our progress over the first four years of this proposal has led to the characterization of part of the PQS synthetic pathway and provided us with information on the regulation and synthesis of PQS, and on the activity exerted by PQS. Overall, the available data indicate that PQS signaling is a complicated and important part of P. aeruginosa cell-to-cell communication. Because of this, we propose experiments that will help to better understand PQS and its role in intercellular signaling. We plan to identify genes that are regulated by PqsR- PQS and to learn how pqsR is controlled. Our studies will also include the functional analysis of PqsE, an effector needed for PQS activity. We plan to continue to characterize the enzymes required for PQS synthesis in order to complete the mapping of the entire metabolic pathway. Finally, we will identify compounds that inhibit PQS synthetic enzymes and will test these compounds for the ability to inhibit virulence in a zebrafish model of P. aeruginosa infection. The completion of these studies will further our understanding of quinolone signaling and should provide a solid foundation to pursue future studies aimed at developing novel therapeutic treatments for P. aeruginosa.