Therapies of infections caused by gram-positive bacteria

革兰氏阳性菌引起的感染的治疗

• 批准号: 7672012
• 负责人: Dominique M. Missiakas
• 金额: $ 59.58万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 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/7672012
• 关键词: Address; American; Amides; Anabolism; Animal Model; Anthrax disease; Anti-Infective Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacillus anthracis; Bacillus anthracis spore; Biochemical; Bioinformatics; Biological Factors; Cell Wall; Chicago; Communities; Development; Drug resistance; Engineering; Enzymes; Gram-Positive Bacteria; Growth; Homologous Gene; Human; Hydrolase; Infection; Infectious Agent; Intervention; Iron; Laboratories; Lead; Measures; Michigan; Microbe; Molecular; Molecular Genetics; Organic Chemistry; Pathogenesis; Pathway interactions; Physiological; Population; Property; Protein Inhibition; Proteins; Research; Research Personnel; Research Project Grants; Role; Siderophores; Staphylococcus aureus; Structure; System; Teichoic Acids; Testing; Therapeutic; United States; Universities; adenylate; assay development; biodefense; capsule; high throughput screening; human disease; human morbidity; human mortality; in vitro Assay; infectious disease model; inhibitor/antagonist; lipoteichoic acid; methicillin resistant Staphylococcus aureus; mutant; pathogen; petrobactin; small molecule; sortase; trait

Gram-positive bacterial pathogens inflict an enormous burden of human disease world-wide. This closely related group of microbes includes Bacillus anthracis, the most notorius bioterror agent, as well as Staphylococcus aureus, which, judged by human morbidity, is currently the single most important infectious agent in the United States. Broad dissemination of antibiotic (methicillin) resistant S. aureus (MRSA) strains in American communities implies the return of the pre-antibiotic era unless new therapies can reduce human mortality. B. anthracis has been weaponized and engineered to acquire antibiotic resistance traits that render currently available antibiotics ineffective and human populations defenseless, if they had been exposed to drug-resistant anthrax spores. The GLRCE Research Project 3 proposal addresses the need for new antibiotics by unraveling molecular mechanisms that lead to assembly of siderophores, proteins, capsules or teichoic acids in the cell wall envelope of B. anthracis and S. aureus. Biosynthesis of all four types of compounds is either essential for bacterial growth or absolutely required for the pathogenesis of infection. An interdisciplinary team of researchers at Argonne National Laboratory, the University of Michigan and the University of Chicago applies multiple different technological platforms to focus on these questions: bioinformatics, molecular genetics, biochemical purification and assay development, structure determination, organic chemistry and small molecule inhibition, as well as infectious disease modeling. Products of this research are the in depth molecular appreciation of envelope function and pathogenesis in B. anthracis and S. aureus and the identification of small molecule inhibitors that will be tested for their property of antiinfective or antibiotic therapies. The specific aims are: 1. Inhibition of capsular biosynthesis in Bacillus anthracis; 2. Inhibition of lipoteichoic acid biosynthesis in Bacillus anthracis and MRSA; 3. Inhibition of iron siderophore biosynthetic pathways in Bacillus anthracis and MRSA; 4. Inhibition of protein assembly pathways in the envelope of Bacillus anthracis and MRSA; 5. Inhibition of siderophore amide hydrolases in B. anthracis and MRSA.

革兰氏阳性细菌病原体在世界范围内造成人类疾病的巨大负担。这么近 相关的微生物组包括炭疽杆菌（最臭名昭著的生物恐怖剂），以及 金黄色葡萄球菌，根据人类发病率判断，是目前唯一最重要的传染性疾病， 在美国的代理人。广泛传播的抗生素（甲氧西林）耐药的S。金黄色葡萄球菌（MRSA）菌株 在美国社区，除非新的治疗方法可以减少人类感染，否则意味着前抗生素时代的回归。 mortality. B。炭疽菌已经被武器化并被改造以获得抗生素抗性特征， 使目前可用的抗生素无效，使人类无法防御， 暴露在抗药性炭疽孢子中GLRCE研究项目3提案解决了以下需求： 通过解开导致铁载体，蛋白质， 在B的细胞壁被膜中的荚膜或磷壁酸。anthracis和S.金黄色。四种生物合成 这些类型的化合物要么是细菌生长所必需的，要么是细菌致病所绝对需要的。 感染一个跨学科的研究小组在阿贡国家实验室，大学 密歇根大学和芝加哥大学应用多种不同的技术平台来关注这些问题， 问题：生物信息学，分子遗传学，生化纯化和检测开发，结构 测定、有机化学和小分子抑制以及传染病建模。 这项研究的成果是深入的包膜功能和发病机制的分子评价， B。anthracis和S.金黄色葡萄球菌和鉴定小分子抑制剂，将测试其 抗感染或抗生素治疗的性质。具体目标是：1.抑制荚膜生物合成 炭疽杆菌; 2.炭疽杆菌和MRSA中脂磷壁酸生物合成的抑制; 3.抑制 炭疽杆菌和MRSA中铁载体生物合成途径的研究; 4.蛋白质组装的抑制 炭疽杆菌和MRSA包膜中的途径; 5.铁载体酰胺水解酶的抑制 B。炭疽菌和MRSA。