Peptide autoinducers of staphylococcal pathogenicity.

葡萄球菌致病性肽自诱导剂。

• 批准号: 8586287
• 负责人: Richard P. Novick
• 金额: $ 47.38万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8586287
• 关键词: Active Sites; Affect; Agonist; Amino Acids; Attenuated; Bacterial Proteins; Binding; Binding Sites; Biochemical; Biological; Biological Assay; C-terminal; Cellular biology; Communities; Complex; Disease; Distal; Genetic; Goals; Histidine; Hospitals; In Vitro; Infection; Invaded; Learning; Ligand Binding; Ligands; Maps; Membrane; Methods; Molecular; Mutagenesis; Organism; Outcome; Pathogenesis; Pathogenicity; Peptides; Phosphorylation; Phosphotransferases; Production; Prokaryotic Cells; Protein Secretion; Proteins; Protomer; Receptor Activation; Receptor Inhibition; Resistance; Role; Scourge; Side; Signal Transduction; Site; Specificity; Staphylococcus aureus; Stress; Structure; System; Testing; Therapeutic; Toxin; Treatment Efficacy; Variant; Virulence; contagion; crosslink; design; dimer; mutant; novel; programs; protein-histidine kinase; public health relevance; quorum sensing; receptor; receptor binding; receptor function; tool; transmission process

DESCRIPTION (provided by applicant): The agr locus encodes the central regulatory system for staphylococcal pathogenesis and other stress-related functions. It is a quorum-sensing system that contains a two-component signal transduction module, encoded by agrA and C, and a peptide autoinducer (AIP), encoded by agrD, that is the activating ligand. Natural variants exist that cross inhibit agr autoinduction in heterologous combinations, thus blocking pathogenesis. This is the continuation of a long-term program whose overall goal is to understand the mechanism of agr autoinduction, the role of the agr autoinduction circuit in the pathogenesis of staphylococcal disease, the therapeutic potential of agr inhibition, and the biological significance of agr variants and their biotypes. Specific Aims for this period are: 1. To determine mechanisms of peptide secretion, binding, activation and inhibition. 2. To determine the mechanism of signal transduction in the agr system. 3. To determine the therapeutic potential of agr inhibition. Design and Methods. Genetic and biochemical methods will be used to determine the mechanism of AIP secretion. A direct ligand-binding assay will be used to analyze receptor-ligand interactions. Specific ligand binding sites will be identified by mutagenesis and cross-linking studies; the mechanism of receptor activation will be determined by mutational and structural studies. Constitutively active receptor mutants will be an important tool in vitro mechanistic studies. Mutants resistant to inverse agonism will be isolated and analyzed to test the hypothesis that there are specific inhibitory contacts as well as activating contacts. The hypothesis will be tested that administration of an inhibitory AIP at a distal site can block the establishment of an experimental infection, or if administered after an infection has been established, can attenuate or eradicate the infection.

描述（由申请人提供）：AGR基因座编码用于葡萄球菌发病机理和其他与压力相关功能的中央调节系统。它是一个群体感应系统，包含由AGRA和C编码的两组分组信号转导模块，以及由Agrd编码的肽自动引导者（AIP），即激活配体。存在自然变体，可以跨差异组合中的AGR自动诱导，从而阻断发病机理。这是一个长期计划的延续，其总体目标是了解AGR自动诱导的机制，AGR自动诱导电路在葡萄球菌疾病的发病机理中的作用，AGR抑制的治疗潜力以及AGR变体及其生物型的生物学意义。在此期间的具体目的是：1。确定肽分泌，结合，激活和抑制的机制。 2。确定AGR系统中信号转导的机理。 3。确定AGR抑制的治疗潜力。设计和方法。遗传和生化方法将用于确定AIP分泌的机理。直接的配体结合测定法将用于分析受体配体相互作用。特定的配体结合位点将通过诱变和交联研究来识别。受体激活的机制将由突变和结构研究确定。组成性活跃的受体突变体将是体外机械研究的重要工具。将分离并分析对反向激动剂的突变体，以检验以下假设：存在特定的抑制接触以及激活接触。该假设将进行检验，远端部位的抑制性AIP可以阻止实验感染的建立，或者如果在建立感染后给药，可以减弱或消除感染。