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.

革兰氏阳性细菌病原体给全世界人类带来了巨大的疾病负担。这密切 相关的微生物群包括炭疽杆菌，最臭名昭著的生物恐怖剂，以及 从人类发病率来看，金黄色葡萄球菌是目前最重要的单一传染病 在美国的代理。抗生素（甲氧西林）耐药金黄色葡萄球菌（MRSA）菌株的广泛传播 在美国社区意味着抗生素前时代的回归，除非新疗法能够减少人类 死亡。炭疽芽孢杆菌已被武器化和改造以获得抗生素抗性特征， 如果使用的话，现有的抗生素将失效，人类将毫无防御能力 接触抗药性炭疽孢子。 GLRCE 研究项目 3 提案解决了以下需求： 通过揭示导致铁载体、蛋白质组装的分子机制来开发新的抗生素 炭疽芽孢杆菌和金黄色葡萄球菌细胞壁包膜中的胶囊或磷壁酸。所有四种物质的生物合成 化合物类型要么是细菌生长所必需的，要么是细菌发病机制所必需的 感染。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种不同的技术平台来专注于这些 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，以及传染病模型。 这项研究的成果是对包膜功能和发病机制的深入分子评价。 炭疽芽孢杆菌和金黄色葡萄球菌以及将测试其作用的小分子抑制剂的鉴定 抗感染或抗生素疗法的特性。具体目标是： 1. 抑制荚膜生物合成 炭疽杆菌； 2.抑制炭疽杆菌和MRSA的脂磷壁酸生物合成； 3. 抑制 炭疽杆菌和 MRSA 中铁铁载体生物合成途径的研究； 4. 抑制蛋白质组装 炭疽杆菌和 MRSA 包膜中的途径； 5. 铁载体酰胺水解酶的抑制 炭疽杆菌和 MRSA。