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

铜绿假单胞菌细胞间信号PQS的研究

• 批准号: 8918410
• 负责人: EVERETT C PESCI
• 金额: $ 37.63万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8918410
• 关键词: Affinity Chromatography; Age; Antibiotics; Bacteria; Biochemical; Biological Assay; Cell Communication; Cell physiology; Cells; Chemicals; Cystic Fibrosis; DNA; Data; Detection; Enzymes; Foundations; Future; Gene Cluster; Gene Expression; Genes; Genetic; Goals; Health; Human; Immune response; Indium; Individual; Infection; Insecta; Kynurenine; Learning; Lung; Mammals; Maps; Mass Spectrum Analysis; Metabolic Pathway; Modeling; Motivation; Nosocomial Infections; Nucleic Acid Regulatory Sequences; Operon; Pathway interactions; Plants; Process; Production; Promoter Regions; Protein Binding; Proteins; Pseudomonas; Pseudomonas aeruginosa; Quinolones; Regulation; Research; Role; Signal Pathway; Signal Transduction; Solid; Synthetic Genes; System; Testing; Translational Repression; Tryptophan; Virulence; Virulence Factors; Zebrafish; analog; anthranilate; base; cystic fibrosis patients; design; human disease; inhibitor/antagonist; intercellular communication; metabolomics; mutant; novel; novel therapeutics; pathogen; protein function; research study; small molecule; synthetic enzyme; therapy design

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.

描述（由申请方提供）：铜绿假单胞菌是一种机会致病菌，是囊性纤维化（CF）患者院内感染和肺部感染的主要原因。这种无处不在的细菌以多种方式适应其周围环境，其中之一是利用小的化学化合物作为细胞与细胞通信的信号。这些信号控制许多细胞功能，在感染过程中很重要。该提案将集中于喹诺酮信号系统，其利用假单胞菌喹诺酮信号（PQS; 2-庚基-3-羟基-4-喹诺酮）作为转录调节因子PqsR的共诱导物。PqsR-PQS积极调节喹诺酮类药物的生产和许多感染所需的毒力因子。PQS也在感染的CF患者的肺中产生，这意味着喹诺酮信号传导在人类疾病中起作用。我们在这一提议的前四年的进展导致了部分PQS合成途径的表征，并为我们提供了有关PQS的调节和合成以及PQS所发挥的活性的信息。总体而言，现有数据表明PQS信号传导是铜绿假单胞菌细胞间通讯的复杂且重要的部分。正因为如此，我们提出的实验，这将有助于更好地了解PQS及其在细胞间信号传导的作用。我们计划鉴定受PqsR-PQS调控的基因，并了解pqsR是如何被控制的.我们的研究还将包括PqsE的功能分析，PqsE是PQS活性所需的效应子。我们计划继续表征PQS合成所需的酶，以完成整个代谢途径的定位。最后，我们将鉴定抑制PQS合成酶的化合物，并测试这些化合物在铜绿假单胞菌感染的斑马鱼模型中抑制毒力的能力。这些研究的完成将进一步加深我们对喹诺酮类药物信号传导的理解，并为未来研究铜绿假单胞菌的新治疗方法提供坚实的基础。