A High-Throughput Screen for Modulators of Quorum Sensing in Vibrio cholerae

霍乱弧菌群体感应调制器的高通量筛选

• 批准号: 8136369
• 负责人: BONNIE L BASSLER
• 金额: $ 2.5万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-15 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8136369
• 关键词: Agonist; Anti-Bacterial Agents; Bacteria; Biochemistry; Biological; Biological Assay; Bioluminescence; Cell Communication; Cells; Chemicals; Cholera; Clear Cell; Clinical Microbiology; Data; Detection; Development; Disease; Drug Design; Ensure; Follow-Up Studies; Goals; Health; Human; In Vitro; Industrial Microbiology; Intervention; Investigation; Lead; Light; Marines; Microbe; Microbial Biofilms; Microbiology; Molecular; Molecular Chaperones; Molecular Probes; Organic Chemistry; Process; Production; Proteins; RNA; Research; Screening procedure; Series; Signal Transduction; Structure-Activity Relationship; System; Testing; Time; Vibrio; Vibrio cholerae; Virulence; Virulence Factors; Work; X-Ray Crystallography; bacterial genetics; base; follow-up; high throughput screening; improved; inhibitor/antagonist; microorganism; mutant; novel; pathogen; pathogenic bacteria; quorum sensing; receptor; response; small molecule; tool

DESCRIPTION (provided by applicant): The long-term goal of this research is to explore the molecular mechanisms that bacteria use for cell-cell communication (i.e., quorum sensing). Until recently, the ability of bacteria to communicate was considered an anomaly that occurred only in a few marine Vibrio species. It is now clear that cell-cell communication is the norm in the bacterial world and that understanding this process is fundamental to all of microbiology, including industrial and clinical microbiology. Here we propose an integrative chemical biological study of the quorum-sensing circuit of the human pathogen Vibrio cholerae, the causative agent of the disease cholera. The V. cholerae quorum-sensing circuit depends on the production and detection of a small molecule signals called autoinducers. We propose to collaborate with the MLPCN to identify small molecules that modulate three distinct steps in the quorum-sensing cascade by performing an established high- throughput screen. Follow up secondary screens will define the modes-of-action of these lead compounds and categorize them as: 1. Quorum-sensing receptor agonists; 2. LuxO inhibitors; 3. Hfq inhibitors. Molecules identified through this work will provide new tools to probe the molecular mechanisms governing the quorum-sensing regulatory networks of V. cholerae and other microorganisms. Additionally, these compounds will be used as leads for the development of broad-spectrum antibacterial drugs designed to interfere with quorum sensing. Such therapies could have enormous ramifications for improving human health. PUBLIC HEALTH RELEVANCE: V. cholerae is a globally important pathogen that causes several million cases of disease per year. Our studies have shown that, in order to be pathogenic, V. cholerae must possess an intact quorum-sensing system because cell-cell communication controls the timing underlying production and release of virulence factors and the formation of biofilms. The investigations proposed here will facilitate the development of synthetic strategies for controlling quorum sensing in this important pathogenic microbe and possibly other pathogenic bacteria that use quorum sensing to control virulence.

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（即群体传感）。直到最近，细菌传达的能力才被认为是仅在几种海洋弧菌物种中发生的一种异常。现在很明显，细胞 - 细胞通信是细菌世界中的常态，并且了解这一过程对于包括工业和临床微生物学在内的所有微生物学都是基础的。在这里，我们提出了一项对疾病霍乱的病原体霍乱霍乱具核霍乱弧菌的群体感应回路的综合化学生物学研究。 V.霍乱群体感应电路取决于称为自动诱导剂的小分子信号的产生和检测。我们建议与MLPCN合作，以确定通过执行已建立的高吞吐量屏幕来调节法定感应级联的三个不同步骤的小分子。后续次级筛选将定义这些铅化合物的作用模式，并将其分类为：1。群体感应受体激动剂； 2。卢克索抑制剂； 3。HFQ抑制剂。通过这项工作确定的分子将提供新的工具来探测有关霍乱弧菌和其他微生物的群体感应调节网络的分子机制。此外，这些化合物将用作开发旨在干扰法定人数的广谱抗菌药物的铅。这种疗法可能会对改善人类健康产生巨大的影响。 公共卫生相关性：V。Cholerae是一种全球重要的病原体，每年会引起数百万例疾病。我们的研究表明，为了使病原体，霍乱葡萄球菌必须具有完整的群体感应系统，因为细胞 - 细胞通信控制了毒力因子的下限产生和释放的时间和生物膜的形成。此处提出的研究将促进在这种重要的致病微生物以及可能使用法定人数控制毒力的其他病原菌中控制法定感测的合成策略。