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: 8448669
• 负责人: Dominique M. Missiakas
• 金额: $ 54.17万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448669
• 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.

革兰氏阳性细菌在世界范围内给人类疾病带来了巨大的负担。这么近了 相关的微生物群包括最臭名昭著的生物恐怖因子炭疽芽孢杆菌以及 金黄色葡萄球菌，从人类的发病率来看，是目前最重要的传染病 在美国的特工。耐甲氧西林金黄色葡萄球菌(MRSA)菌株的广泛传播 在美国社区意味着前抗生素时代的回归，除非新的治疗方法可以减少人类 死亡率。炭疽杆菌已经被武器化和改造，以获得抗生素耐药性特征， 使目前可用的抗生素无效，使人类群体手无寸铁，如果它们已经 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， 炭疽杆菌和金黄色葡萄球菌细胞壁被膜中的胶囊或磷壁酸。四种化合物的生物合成 不同类型的化合物对于细菌的生长是必不可少的，或者对于致病是绝对必要的 感染。华盛顿大学阿贡国家实验室的跨学科研究团队 密歇根大学和芝加哥大学应用多个不同的技术平台来关注这些 问题：生物信息学，分子遗传学，生化提纯和分析的发展，结构 测定、有机化学和小分子抑制，以及传染病模型。 本研究的成果是对包膜功能和发病机制的深入分子研究。 炭疽杆菌和金黄色葡萄球菌及其小分子抑制剂的鉴定 抗感染或抗生素治疗的特性。其具体目的是：1.抑制包膜生物合成 炭疽芽孢杆菌；2.抑制炭疽芽孢杆菌和MRSA中脂磷壁酸的生物合成；3.抑制作用 炭疽芽孢杆菌和耐甲氧西林金黄色葡萄球菌铁载体生物合成途径的研究；4.蛋白质组装的抑制 炭疽芽孢杆菌和耐甲氧西林金黄色葡萄球菌包膜中的途径；5.铁载体酰胺水解酶的抑制 炭疽和耐甲氧西林金黄色葡萄球菌