A High-Throughput Screen for LuxS Quorum-Sensing Inhibitors

LuxS 群体感应抑制剂的高通量筛选

• 批准号: 7693093
• 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: 2009
• 资助国家: 美国
• 起止时间: 2009-05-06 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7693093
• 关键词: Amino Acids; Anti-Bacterial Agents; Bacteria; Binding; Biochemistry; Biological; Biological Assay; Cell Communication; Cells; Chemicals; Clear Cell; Clinical Microbiology; Collaborations; Communication; Complement; Complex; Data; Detection; Development; Dose; Drug Design; Enzymes; Follow-Up Studies; Genetic; Goals; Health; Human; Investigation; Kinetics; Lead; Letters; Marines; Mediating; Microbiology; Molecular; Organic Chemistry; Organism; Pharmaceutical Preparations; Process; Production; Protein Inhibition; Research; Signal Pathway; Signal Transduction; Structure; Testing; VAI-2; Vibrio; Work; X-Ray Crystallography; bacterial genetics; base; design; high throughput screening; in vitro Assay; in vivo; inhibitor/antagonist; mutant; periplasm; process optimization; public health relevance; quorum sensing; receptor; small molecule

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, and ultimately to understanding the development of higher organisms. Here we propose an integrative chemical, structural, and biological study of a recently identified quorum-sensing circuit whose functioning depends on the production and detection of a small molecule signal called autoinducer-2 (AI-2). AI-2, unlike other known bacterial auto inducers, is a universal quorum-sensing signal that mediates communication among different bacterial species. We propose to collaborate with the MLPCN to carry out high-throughput screens to identify inhibitors of the AI-2 synthase, LuxS and the AI-2 receptor, LuxPQ. Follow up studies to further characterize the lead compounds identified from the screens will combine synthetic organic chemistry, bacterial genetics, biochemistry, and X-ray crystallography. Antagonists of the AI-2 signaling pathway identified through this work will provide lead compounds for the development of broad-spectrum antibacterial drugs designed to interfere with quorum sensing which could have enormous ramifications for bettering human health. PUBLIC HEALTH RELEVANCE: 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. The investigations proposed here will facilitate the development of synthetic strategies for controlling quorum sensing. Specifically, antagonists of the AI-2 signaling pathway identified through this work will provide lead compounds for the development of broad-spectrum antibacterial drugs which could have enormous ramifications for bettering human health.

描述（由申请人提供）：本研究的长期目标是探索细菌用于细胞间通讯（即群体感应）的分子机制。直到最近，细菌的交流能力还被认为是一种异常现象，只发生在少数海洋弧菌物种中。现在很清楚，细胞间通讯是细菌世界的常态，理解这一过程是所有微生物学的基础，包括工业和临床微生物学，并最终了解高等生物的发育。在这里，我们提出对最近发现的群体感应电路进行综合化学、结构和生物学研究，该电路的功能取决于称为自诱导剂-2 (AI-2) 的小分子信号的产生和检测。与其他已知的细菌自诱导剂不同，AI-2 是一种通用的群体感应信号，可介导不同细菌物种之间的通讯。我们建议与 MLPCN 合作进行高通量筛选，以鉴定 AI-2 合酶 LuxS 和 AI-2 受体 LuxPQ 的抑制剂。后续研究将结合有机合成化学、细菌遗传学、生物化学和 X 射线晶体学，进一步表征从屏幕中识别出的先导化合物。通过这项工作确定的 AI-2 信号通路拮抗剂将为开发旨在干扰群体感应的广谱抗菌药物提供先导化合物，这可能对改善人类健康产生巨大影响。 公共卫生相关性：直到最近，细菌的交流能力还被认为是一种异常现象，只发生在少数海洋弧菌物种中。现在很清楚，细胞间通讯是细菌世界的常态，理解这一过程是所有微生物学（包括工业和临床微生物学）的基础。这里提出的研究将促进控制群体感应的合成策略的开发。具体来说，通过这项工作确定的 AI-2 信号通路拮抗剂将为开发广谱抗菌药物提供先导化合物，这可能对改善人类健康产生巨大影响。