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，美国因传染病造成的死亡率翻了一番。新兴和再 新出现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： 基于针对细菌细胞包膜的针对细菌病原体的创新对策。 该中心将利用哈佛七所顶尖大学的强大协同作用和全面知识 细菌细胞包膜生物学领域的研究人员建立了生产 针对细胞表面碳水化合物的抗菌疫苗以及用于发现抗菌药物。这些 该平台将用于开发土拉弗朗西斯菌、鼻疽伯克霍尔德菌的疫苗。弧菌 霍乱、沙门氏菌、伤寒菌等，并发现杀死抗生素耐药性 ESKAPE 的抗生素 病原体，包括金黄色葡萄球菌、铜绿假单胞菌和鲍曼不动杆菌 抑制细胞包膜靶标。一个疫苗平台将能够合理设计高效疫苗 糖结合疫苗由纯肽和寡糖成分制成，而另一种将提供 快速生产具有成本效益的基于细胞包膜的疫苗作为应对措施的技术 意外的或发展中国家的流行病。抗菌发现项目侧重于不同的细胞 包膜途径和病原体，但所有三个项目的基石是一个高效的新范例 用于高通量筛选，结合了传统方法的优点，同时克服了缺点 基于靶标和细胞的筛选方法。我们的目标是为开发渠道提供可交付成果 至少一种新疫苗和 3-5 种抗菌化合物已验证细胞包膜靶标，并且 在动物模型中证明功效 - 同时在基础方面取得重大进展 细胞膜生物学科学。 CETR 的调查人员是各自领域的领导者， 包括一个具有不同寻常的科学广度和成就的多学科团队 自从 PI 领导了非常成功的 NERCE 项目以来，拥有全面的管理经验。 研究人员的科学专业知识包括免疫学、分子发病机制、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、有机合成 化学、基因组方法、高通量筛选/后续化学、抗生素作用机制 和耐药性以及疫苗开发。