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 群体感应（Quorum sensing，QS）是许多细菌利用细胞间通讯系统调控基因表达的一种机制 以协调的方式表达。我们的工作主要集中在铜绿假单胞菌的QS系统， 一种人类的寄生菌和机会致病菌。铜绿假单胞菌使用QS来调节数十种 基因，包括几个重要的毒力因子。铜绿假单胞菌QS由转录介导， 响应酰基高丝氨酸内酯信号的因子LasR和RhlR，以及响应酰基高丝氨酸内酯信号的因子PqsR。 alkylquuniolone信号。铜绿假单胞菌中QS的初始表征描述了一个层次结构：LasR 调节RhlR和PqsR活性。在过去的几年里，我们和其他人已经表明， 等级制度是可塑的。RhlR和PqsR在分离株中不存在功能性LasR的情况下可以具有活性 在许多情况下，特别是那些孤立于囊性纤维化患者的慢性肺部感染的情况下， （CF）。这些结果表明，QS的“重新布线”对于维持细菌的毒力功能至关重要。 慢性感染 这一建议建立在我们以前的观察，询问这个替代的生物学意义 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 菌株问i）铜绿假单胞菌的QS结构如何改变？（二）在这种变化的等级制度中，如何 RhlR和PqsR QS是否相互作用影响慢性感染分离株的毒力功能？以及iii） 一个高度保守的、均匀的QS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在铜绿假单胞菌中的核心重要性， 慢性感染，并告知未来的努力，设计治疗靶向RhlR或PQS QS在这一领域。 细菌。