Innovative Platforms for Antimicrobial Therapy and Vaccine Development

抗菌治疗和疫苗开发的创新平台

• 批准号: 8791872
• 负责人: Dennis L. Kasper
• 金额: $ 493.25万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8791872
• 关键词: Acinetobacter baumannii; Animal Model; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Area; Biochemistry; Biology; Burkholderia pseudomallei; Carbohydrates; Cell surface; Cells; Chemistry; Communicable Diseases; Development; Enzymatic Biochemistry; Epidemic; Francisella tularensis; Genomics; Glycobiology; Ice; Infection; Infection prevention; Instruction; Knowledge; Methods; Molecular Genetics; Molecular Immunology; Oligosaccharides; Organic Chemistry; Organism; Pathogenesis; Pathway interactions; Peptides; Populations at Risk; Production; Pseudomonas aeruginosa; Research Personnel; Research Support; Resistance; Salmonella typhi; Science; Staphylococcus aureus; Technology; Translational Research; Translations; United States; Vaccines; Vibrio cholerae; antimicrobial; base; cell envelope; combat; cost effective; design; experience; follow-up; high throughput screening; innovation; killings; mortality; multidisciplinary; novel; novel strategies; novel vaccines; pathogen; programs; screening; therapy development; vaccine development

Since 1980 the mortality rate due to infectious disease in the United States has doubled. Emerging and re emerging bacterial pathogens are a major cause of the increased mortality and there is an urgent need for new approaches to combat these pathogens. We propose to establish a Center for Excellence in Translational Research that supports five projects organized around a single theme: the development of innovative countermeasures against bacterial pathogens based on targeting the bacterial cell envelope. The Center will leverage the powerful synergies and comprehensive knowledge of seven leading Harvard investigators in the area of bacterial cell envelope biology to establish novel platforms for the production of antibacterial vaccines targeting cell surface carbohydrates and for the discovery of antibacterials. These platforms will be used to develop vaccines for Francisella tularensis, Burkholderia pseudomallei. Vibrio cholerae, and Salmonella, typhi among others, and to discover antibiotics that kill antibiotic resistant ESKAPE pathogens, including Staphylococcus aureus, Pseudomonas aeruginosa, and Acinetobacter baumannii, by inhibiting cell envelope targets. One vaccine platform will enable rational design of highly effective glycocpnjugate vaccines from pure peptide and oligosaccharide components, while the other will provide technologies to rapidly produce cost-effective cell envelope-based vaccines as countermeasures for unexpected or developing-world epidemics. The antibacterial discovery projects focus on different cell envelope pathways and pathogens, but a cornerstone of all three projects is a highly effective new paradigm for high throughput screening that combines the strengths, while overcoming the weaknesses, of traditional target- and cell-based screening approaches. We aim to provide as deliverables to development pipelines at least one new vaccine and 3-5 antibacterial compounds that have validated cell envelope targets and demonstrate efficacy in animal models - while simultaneously making significant advances in the underlying science of cell envelope biology. The CETR investigators are leaders in their respective fields and comprise a multidisciplinary team of unusual scientific breadth and accomplishment as well as comprehensive administrative experience since the PI led the highly successful NERCE program. Scientific expertise of the investigators includes immunology, molecular pathogenesis, molecular genetics of both Gram negative and Gram positive organisms, biochemistry/enzymology, glycobiology, synthetic organic chemistry, genomic methods, high throughput screening/follow up chemistry, antibiotic mechanisms of action and resistance, and vaccine development.

自1980年以来，由于传染病而导致的死亡率增加了一倍。新兴和重新 新兴的细菌病原体是死亡率增加的主要原因，迫切需要 对抗这些病原体的新方法。我们建议建立一个卓越中心 转化研究支持围绕一个主题组织的五个项目：发展 基于靶向细菌细胞包膜的细菌病原体的创新对策。 该中心将利用强大的协同作用和七个领先的哈佛大学的全面知识 细菌细胞包膜生物学领域的研究者建立新的平台以生产 靶向细胞表面碳水化合物的抗菌疫苗和抗菌物的发现。这些 平台将用于开发用于弗朗西斯氏菌的疫苗，Burkholderia pseudomallei。弧菌 霍乱和沙门氏菌，Typhi等 病原体，包括金黄色葡萄球菌，铜绿假单胞菌和baumannii的病原体， 抑制细胞包膜靶标。一个疫苗平台将实现高效的合理设计 来自纯肽和寡糖成分的糖氯二轭疫苗，另一个将提供 迅速生产基于成本效益的细胞包膜疫苗作为对策的技术 意外或发展世界流行病。抗菌发现项目集中于不同的细胞 信封途径和病原体，但这三个项目的基石都是一个非常有效的新范式 对于高吞吐量筛查，结合了优势，同时克服了传统的弱点 基于目标和细胞的筛选方法。我们的目标是作为开发管道的可交付成果 至少一种新的疫苗和3-5种验证了细胞包膜靶标和的抗菌化合物 在动物模型中表现出功效 - 同时在基础上取得了重大进步 细胞包膜生物学科学。 Cetr研究人员是各自领域的领导者， 组成了一个多学科的团队，包括不寻常的科学广度和成就以及 自PI以来，全面的行政经验领导了非常成功的Nerce计划。 研究人员的科学专业知识包括免疫学，分子发病机理，分子遗传学 革兰氏阴性和革兰氏阳性生物，生物化学/酶学，糖生物学，合成有机物 化学，基因组方法，高吞吐量筛查/后续化学，抗生素作用机制 和抗性和疫苗开发。