Staphylococcal superantigen and anthrax inhibitors

葡萄球菌超抗原和炭疽抑制剂

基本信息

批准号：
7672097
负责人：
Patrick M Schlievert
金额：
$ 68.57万
依托单位：
UNIVERSITY OF CHICAGO
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：
2009-03-24 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7672097
关键词：
Affinity Anthrax disease Antibiotic Resistance Area Bacillus anthracis Basic Science Binding Binding Sites Categories Cell Separation Collaborations Data Development Disease Dose Engineering Enterotoxins Exotoxins Foundations Funding Genes Goals Grant HLA-DR Antigens Half-Life Homologous Gene Human Immune In Vitro Influenza Intervention Intravenous Intravenous Immunoglobulins Libraries Lung Mediating Molecular Mutagenesis Mutation Organism Oryctolagus cuniculus Oxidation-Reduction Oxygen Participant Pathogenesis Pneumonia Production Proteins Publications Purpura Fulminans Records Regulation Research Personnel Role Staphylococcal Enterotoxin B Staphylococcus aureus Subgroup Superantigens Surface Symptoms System T-Cell Receptor Technology Testing Time Toxic Shock Syndrome Toxin-1 Transmembrane Domain United States Virulence Vitamin K 2 Work Yeasts analog anthrax toxin biodefense capsule cytokine design extracellular in vitro activity in vivo inhibitor/antagonist macrophage methicillin resistant Staphylococcus aureus pathogen prevent programs protein-histidine kinase receptor receptor binding respiratory response sensor small molecule staphylococcal enterotoxin subcutaneous three dimensional structure

项目摘要

Long-term goals are to understand the pathogenesis of methicillin-resistant Staphylococcus aureus (MRSA) that secrete superantigens (SAgs) such as enterotoxin (SE) B or C, SE-like Q, and toxic shock syndrome toxin-1 (TSST-1) and Bacillus anthracis. MRSA are emerging pathogens and their SAgs category B select agents. B. anthracis is a category A select agent. We have assembled two projects that are described below. Project 1. High-Affinity Molecules to Inhibit Superantigen Function. When produced in vivo or when purposely administered, SAgs are exceptionally toxic (TSS symptoms at doses of 0.1 ng/human). Most MRSA associated with post-influenza TSS, necrotizing pneumonia, and purpura fulminans produce SEB, SEC, SE-like Q, and TSST-1. Specific Aim 1. To engineer and characterize V(3-T cell receptor (TCR) regions that bind with high affinity to SAgs and neutralize them, most importantly SEB, SEC, SE-like Q, and TSST-1. Specific Aim 2. To engineer and characterize MHC II regions that bind with high affinity to SAgs and neutralize their activities. Specific Aim 3. To test the ability of soluble Vp-TCRs and MHC Ms to neutralize the activities of SAgs in vitro and in vivo in rabbits. Project. 2: Inhibitors of SrrA-SrrB and BrrA-BrrB Regulated Exotoxin Production. MRSA require oxygen for exotoxin production. This observation led to identification of a "Master Switch" two-component system required for oxygen control of exotoxin production in MRSA. This system, designated srrA-srrB, represses exotoxin production and virulence under conditions of low oxygen. Recently, a homolog in B. anthracis was described-BrrA-BrrB. BrrA-BrrB functions to induce anthrax toxin genes and facilitate disease production. The aims will provide a foundation for interfering with diseases by developing small molecule inhibitors. Specific Aim 4. To characterize SrrB and BrrB as histidine kinases with ability to phosphorylate SrrA and BrrA. Specific Aim 5. To evaluate small molecule inhibitors of SrrB/BrrB to prevent production of SAgs, anthrax toxin, and B. anthracis capsule. Aim 6. To determine the 3-D structures of SrrB and BrrB proteins or extracellular/intracellular domains and combined with menaquinone or inhibitors.

长期目标是了解耐甲氧西林金黄色葡萄球菌（MRSA）的发病机理分泌超抗原（SAGS），例如肠毒素（SE）B或C，类似SE样Q和有毒休克综合征毒素1（TSST-1）和炭疽芽孢杆菌。 MRSA是新兴的病原体，其SAGS类别B选择代理商。 B.炭疽病是选择代理的类别。我们组装了下面描述的两个项目。项目1。高亲和力分子抑制超抗原功能。当在体内或何时生产故意给药的下垂是异常毒性的（TSS症状为0.1 ng/人）。最多 MRSA与后Influenza TSS相关，坏死性肺炎和Purpura Fulminans产生SEB， SEC，类似SE的Q和TSST-1。特定目的1。工程师和表征V（3-T细胞受体（TCR）区域）与高亲和力结合到下垂并中和它们，最重要的是SEB，SEC，SE样Q和TSST-1。具体目的2。工程师和特征MHC II区域，与SAG和SAG相结合的MHC II区域中和他们的活动。特定目标3。测试可溶性VP-TCR和MHC MS中和的能力兔子体外和体内凹陷的活性。项目。 2：调节SRRA-SRRB和BRRA-BRRB的抑制剂外毒素产生。 MRSA需要氧气生产氧气。该观察结果导致了 MRSA中氧毒素产生的氧气控制所需的“主开关”两组分系统。这系统，指定的SRRA-SRRB，在低氧条件下抑制异毒素的产生和毒力。最近，描述了炭疽芽孢杆菌中的同源物。 BRRA-BRRB功能诱导炭疽毒素基因并促进疾病的产生。目的将为干扰疾病的基础产生小分子抑制剂。特定目的4。将SRRB和BRRB表征为组氨酸激酶能够磷酸化SRRA和BRRA的能力。特定目的5。评估SRRB/BRRB的小分子抑制剂防止产生突灭性，炭疽毒素和炭疽芽孢杆菌胶囊的产生。目标6。确定3D结构 SRRB和BRRB蛋白或细胞外/细胞内结构域的组合，并与甲喹酮或抑制剂结合。