Manipulating Quorum Sensing to Control Bacterial Pathogenicity

操纵群体感应来控制细菌致病性

基本信息

批准号：
8435940
负责人：
FREDERICK M HUGHSON
金额：
$ 39.78万
依托单位：
PRINCETON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8435940
关键词：
Agonist Amino Acid Sequence Anti-Bacterial Agents Bacteria Behavior Behavior Control Binding Biochemical Biochemistry Biological Assay Caenorhabditis elegans Cell Communication Cell physiology Cells Chromobacterium Communication Communities Complex Crystallography DNA DNA Binding DNA-Directed RNA Polymerase Data Development Discrimination Drug Design Foundations Genetic Screening Genetic Transcription Goals Growth Human In Vitro Infection Investigation Knowledge Lead Libraries Ligands Microbial Biofilms Molecular Molecular Conformation Mus Mutagenesis Organic Chemistry Pathogenicity Pharmaceutical Preparations Process Proteins Proteolysis Pseudomonas aeruginosa Research Resolution Screening procedure Sensory Signal Transduction Structure Synthesis Chemistry Therapeutic Therapeutic Uses Two-Hybrid System Techniques Universities Virulence Factors Work analog bacterial genetics bacterial resistance base chemical genetics chemical synthesis clinically relevant combat crosslink design follow-up high throughput screening in vivo inhibitor/antagonist mouse model novel pathogen quorum sensing receptor small molecule small molecule libraries tool transmission process

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this research is to explore the molecular mechanisms that bacteria use for cell-cell communication, and to use this knowledge to design broad-spectrum quorum sensing antagonists with potential therapeutic uses. Here we propose a cross-disciplinary investigation of LuxR-type quorum-sensing receptors from two human pathogens, Chromobacterium violaceum and Pseudomonas aeruginosa. We propose to combine synthetic organic chemistry, bacterial genetics, biochemistry and x-ray crystallography to identify and characterize signaling antagonists; these antagonists will serve as lead compounds for the development of antibacterial drugs designed to modulate quorum sensing. In our first aim, we will use high-throughput screening and in vivo assays to identify novel quorum-sensing antagonists active in C. violaceum. In our second aim, we will investigate the mechanisms by which these antagonists function using biochemical assays and x-ray crystallography. This work draws upon extensive preliminary data and provides a foundation for efforts to optimize the antagonists discovered in the first aim. The third aim extends the scope of this work to the clinically important bacterium P. aeruginosa. We propose a similar array of approaches to identify and characterize antagonists of its LuxR-type quorum-sensing receptor. Potent antagonists will be evaluated in a mouse infection assay with the aim of moving forward lead molecules for development into novel anti-bacterial therapeutics.

描述（由申请人提供）：这项研究的长期目标是探索细菌用于细胞 - 细胞通信的分子机制，并利用这些知识来设计具有潜在治疗用途的广谱群体传感拮抗剂。在这里，我们提出了来自两种人类病原体，紫杉醇和铜绿假单胞菌的luxR型群体感应受体的跨学科研究。我们建议结合合成有机化学，细菌遗传学，生物化学和X射线晶体学以识别和表征信号拮抗剂。这些拮抗剂将用作开发旨在调节法定感应的抗菌药物的铅化合物。在我们的第一个目标中，我们将使用高通量筛选和体内测定法来识别活跃于C. violaceum中的新型Quorum-Sensing拮抗剂。在我们的第二个目标中，我们将研究这些拮抗剂使用生化测定和X射线晶体学发挥作用的机制。这项工作借鉴了广泛的初步数据，并为优化第一个目标发现的拮抗剂而努力为基础。第三个目标将这项工作的范围扩展到了临床上重要的铜绿假单胞菌。我们提出了类似的方法来识别和表征其LuxR型Quorum-sensing受体的拮抗剂。将在小鼠感染测定中评估有效的拮抗剂，其目的是将铅分子推向新型抗细菌疗法。