Quinolone and acyl-homoserine lactone quorum sensing in chronic P. aeruginosa infections

慢性铜绿假单胞菌感染中的喹诺酮和酰基高丝氨酸内酯群体感应

• 批准号: 10711652
• 负责人: Ajai Dandekar
• 金额: $ 43.84万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-06 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711652
• 关键词: Acute; Animal Model; Architecture; Attention; Automobile Driving; Bacteria; Bacterial Antibiotic Resistance; Bacterial Infections; Binding; Biological; Cell Communication; Cell Density; Cell physiology; Cells; Chronic; Clinical; Code; Culture Techniques; Cystic Fibrosis; Development; Enzymes; Future; Gene Cluster; Gene Expression; Gene Expression Regulation; Genes; Genetic Diseases; Immune; Infection; Laboratories; Link; Liquid substance; Lung; Lung infections; Maintenance; Mediating; Microbial Biofilms; Modeling; Mutation; Patients; Persons; Population Density; Production; Pseudomonas; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Quinolones; Regulation; Role; Signal Transduction; System; Testing; Virulence; Virulence Factors; Work; acute infection; azetidine; chronic infection; cystic fibrosis infection; design; falls; fitness; gene conservation; genetic analysis; homoserine lactone; human pathogen; interest; lonely individuals; novel therapeutics; opportunistic pathogen; peptide synthase; quorum sensing; receptor; therapeutic target; transcription factor; transcriptome

Project Summary Quorum sensing (QS) is a cell-cell communication system used by many bacteria to regulate gene expression in a coordinated manner. Our work focuses on the QS system of Pseudomonas aeruginosa, a saprophyte and opportunistic pathogen of humans. P. aeruginosa uses QS to regulate dozens of genes, including several important virulence factors. P. aeruginosa QS is mediated by the transcription factors LasR and RhlR, which respond to acyl-homoserine lactone signals, and PqsR, which responds to alkylquniolone signals. Initial characterizations of QS in P. aeruginosa described a hierarchy: LasR regulates RhlR and PqsR activity. Over the past several years we, and others, have shown that this hierarchy is malleable. RhlR and PqsR can be active in the absence of functional LasR in isolates from many settings, particularly those isolated from the chronic lung infections of people with cystic fibrosis (CF). These results suggest a “rewiring” of QS that is critical to the maintenance of virulence functions in chronic infections. This proposal builds on our previous observations to ask about the biological significance of this alternate hierarchy in bacterial isolates from people with CF. We make use of CF isolates and a laboratory model strain to ask i) how is the architecture of QS of P. aeruginosa altered?; ii) in this altered hierarchy, how do RhlR and PqsR QS interact to effect virulence functions in isolates from chronic infection?; and iii) what is the role of a highly-conserved, uniformly QS regulated, non-ribosomal peptide synthetase? The answers to these questions will define the central importance of RhlR and PqsR in P. aeruginosa from chronic infections and inform future efforts to design therapeutics targeting RhlR or PQS QS in this bacterium.

项目摘要 法定人数灵敏度（QS）是许多细菌用于调节基因的细胞电池通信系统 以协调的方式表达。我们的工作着重于铜绿假单胞菌的QS系统， 人类的腐生和机会性病原体。铜绿假单胞菌使用QS调节数十个 基因，包括几种重要的病毒因素。铜绿假单胞菌QS由转录介导 因子LASR和RHLR，对酰基 - 双塞林内酯信号和PQSR作出响应，对此响应于 烷基水信号。铜绿假单胞菌中QS的初始字符描述了一个层次结构：LASR 调节RHLR和PQSR活性。在过去的几年中，我们和其他人都表明了这一点 层次结构是可延展的。 RHLR和PQSR可以在没有功能性LASR的情况下活跃 许多环境，特别是那些从囊性纤维化的人的慢性肺部感染中孤立的情况 （CF）。这些结果表明QS的“重新布线”对于维持病毒功能至关重要 慢性感染。 这项建议是基于我们以前的观察，询问了这种替代方案的生物学 来自CF患者的细菌分离株的层次结构。我们利用CF分离株和实验室模型 问i）铜绿假单胞菌的QS结构如何改变？ ii）在此改变的层次结构中，如何 RHL和PQSR QS是否相互作用以影响慢性感染的分离株中的病毒功能？和iii） 高度保存，均匀调节的非核糖体肽合成酶的作用是什么？ 这些问题的答案将定义RHLR和PQSR在P. eruginosa中的核心重要性 慢性感染和信息未来的努力，以设计针对RHL或PQS QS的治疗剂 细菌。