Innovative Platforms for Antimicrobial Therapy and Vaccine Development

描述(申请人提供)：自1980年以来，美国的传染病死亡率翻了一番。新出现和再次出现的细菌病原体是死亡率上升的主要原因，迫切需要新的方法来对抗这些病原体。我们建议建立一个翻译研究卓越中心，支持围绕单一主题组织的五个项目：基于针对细菌细胞膜的针对细菌病原体的创新对策的开发。该中心将利用哈佛大学在细菌细胞被膜生物学领域的七位领先研究人员的强大协同效应和全面知识，为生产针对细胞表面碳水化合物的抗菌疫苗和发现抗菌药物建立新的平台。这些平台将被用于开发图拉氏方济氏菌、假单胞菌、霍乱弧菌和伤寒沙门氏菌等疫苗，并通过抑制细胞包膜靶点发现可以杀死耐抗生素的ESKAPE病原体的抗生素，包括金黄色葡萄球菌、铜绿假单胞菌和鲍曼不动杆菌。一个疫苗平台将使从纯肽和低聚糖成分中合理设计高效的糖结合疫苗成为可能，而另一个平台将提供快速生产具有成本效益的基于细胞膜的疫苗的技术，作为应对意外或发展中国家流行病的对策。抗菌发现项目侧重于不同的细胞被膜途径和病原体，但所有三个项目的基石是一种用于高通量筛选的高效新范式，它结合了传统靶标和基于细胞的筛查方法的优点，同时克服了缺点。我们的目标是向开发管道提供至少一种新疫苗和3-5种抗菌化合物，这些疫苗已经验证了细胞被膜靶标，并在动物模型中证明了有效性-同时在细胞被膜生物学的基础科学方面取得了重大进展。CETR的调查人员是各自领域的领导者，他们组成了一个多学科团队，具有非凡的科学广度和成就以及全面的管理经验，因为PI领导了非常成功的NERCE项目。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生物的分子遗传学、生物化学/酶学、糖生物学、合成有机化学、基因组方法、高通量筛选/跟踪化学、抗生素的作用机制和耐药性，以及疫苗开发。

DESCRIPTION (provided by applicant): Since 1980 the mortality rate due to infectious disease in the United States has doubled. Emerging and reemerging 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 glycoconjugate 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.