A High-Throughput Screen for LuxS Quorum-Sensing Inhibitors
LuxS 群体感应抑制剂的高通量筛选
基本信息
- 批准号:7693093
- 负责人:
- 金额:$ 2.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Amino AcidsAnti-Bacterial AgentsBacteriaBindingBiochemistryBiologicalBiological AssayCell CommunicationCellsChemicalsClear CellClinical MicrobiologyCollaborationsCommunicationComplementComplexDataDetectionDevelopmentDoseDrug DesignEnzymesFollow-Up StudiesGeneticGoalsHealthHumanInvestigationKineticsLeadLettersMarinesMediatingMicrobiologyMolecularOrganic ChemistryOrganismPharmaceutical PreparationsProcessProductionProtein InhibitionResearchSignal PathwaySignal TransductionStructureTestingVAI-2VibrioWorkX-Ray Crystallographybacterial geneticsbasedesignhigh throughput screeningin vitro Assayin vivoinhibitor/antagonistmutantperiplasmprocess optimizationpublic health relevancequorum sensingreceptorsmall molecule
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 (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):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 - 细胞的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,最终是了解较高生物体的发展。在这里,我们提出了一个最近确定的群体感应电路的集成化学,结构和生物学研究,其功能取决于称为自动引导剂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信。我们建议与MLPCN合作进行高通量屏幕,以鉴定AI-2合酶,Luxs和AI-2受体LuxPQ的抑制剂。后续研究以进一步表征从筛选中确定的铅化合物将结合合成有机化学,细菌遗传学,生物化学和X射线晶体学。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铅化合物,这可能会对改善人类健康产生巨大的影响。
公共卫生相关性: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。这里提出的调查将促进制定控制法定感应的合成策略。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的发展提供铅化合物,这些药物可能具有巨大的后果,以改善人类健康。
项目成果
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BONNIE L BASSLER其他文献
BONNIE L BASSLER的其他文献
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{{ truncateString('BONNIE L BASSLER', 18)}}的其他基金
Intra- and Inter- Species Communication in Bacteria
细菌的种内和种间通讯
- 批准号:
10305584 - 财政年份:2020
- 资助金额:
$ 2.5万 - 项目类别:
Intra- and Inter- Species Communication in Bacteria
细菌的种内和种间通讯
- 批准号:
10529304 - 财政年份:2020
- 资助金额:
$ 2.5万 - 项目类别:
Quantitative Imaging and Analysis of Bacterial Biofilms from the Single Cell to the Collective
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9803916 - 财政年份:2019
- 资助金额:
$ 2.5万 - 项目类别:
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 - 财政年份:2011
- 资助金额:
$ 2.5万 - 项目类别:
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