A High-Throughput Screen for LuxS Quorum-Sensing Inhibitors

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的分子机制（即，群体感应）。直到最近，细菌的交流能力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，细胞间的交流是细菌世界的常态，理解这一过程对所有微生物学，包括工业和临床微生物学，以及最终理解高等生物的发展至关重要。在这里，我们提出了一个综合的化学，结构和生物学研究最近确定的群体感应电路，其功能取决于生产和检测的小分子信号称为autoinducer-2（AI-2）。AI-2与其他已知的细菌自动诱导物不同，是一种通用的群体感应信号，介导不同细菌物种之间的通信。我们建议与MLPCN合作进行高通量筛选，以确定AI-2合酶，LuxS和AI-2受体，LuxPQ的抑制剂。后续研究将结合联合收割机合成有机化学、细菌遗传学、生物化学和X射线晶体学，进一步表征从筛选中鉴定出的先导化合物。通过这项工作确定的AI-2信号通路的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，细胞间的交流是细菌世界的常态，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。这里提出的调查将促进控制群体感应的合成策略的发展。具体而言，通过这项工作确定的AI-2信号通路的拮抗剂将为开发广谱抗菌药物提供先导化合物，这些抗菌药物可能对改善人类健康产生巨大影响。

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.