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。新兴市场和新兴市场