Innovative Platforms for Antimicrobial Therapy and Vaccine Development

自1980年以来，美国传染病死亡率翻了一番。新兴和再生 新出现的细菌病原体是死亡率增加的主要原因， 对抗这些病原体的新方法。我们建议设立一个卓越中心， 转化研究，支持围绕一个主题组织的五个项目： 基于靶向细菌细胞包膜的针对细菌病原体的创新对策。 该中心将充分利用哈佛七个领先大学的强大协同作用和全面知识， 研究人员在细菌细胞包膜生物学领域建立新的平台， 针对细胞表面碳水化合物的抗菌疫苗和抗菌剂的发现。这些 这些平台将用于开发土拉热弗朗西丝菌、类鼻疽伯克霍尔德菌的疫苗。弧菌 霍乱，沙门氏菌，伤寒等，并发现抗生素，杀死抗生素耐药ESKAPE 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， 抑制细胞包膜靶点。一个疫苗平台将使合理设计的高效 糖缀合物疫苗来自纯肽和寡糖组分，而另一种将提供 技术，以迅速生产成本效益高的基于细胞的疫苗作为对策， 发展中国家的突发性流行病抗菌发现项目集中在不同的细胞 包封途径和病原体，但所有三个项目的基石是一个高效的新范式 对于高通量筛选，其结合了传统方法的优点，同时克服了传统方法的缺点， 靶向和细胞筛选方法。我们的目标是为开发管道提供可交付成果 至少一种新疫苗和3-5种具有经验证的细胞包膜靶点的抗菌化合物， 在动物模型中证明疗效-同时在基础研究中取得重大进展 细胞包膜生物学的科学。CETR调查人员是各自领域的领导者， 组成了一个多学科的团队，具有不同寻常的科学广度和成就， 自PI领导非常成功的NERCE计划以来，他拥有全面的行政经验。 研究人员的科学专长包括免疫学、分子发病机制、 革兰氏阴性和革兰氏阳性微生物，生物化学/酶学，糖生物学，合成有机 化学、基因组学方法、高通量筛选/后续化学、抗生素作用机制 以及疫苗的研发。

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.