Center to develop therapeutic countermeasures to high-threat bacterial agents

描述(申请人提供)：多药耐药(MDR)细菌感染的流行继续困扰着全球和美国的医疗保健，由于几乎没有新药从减少的流水线进入市场，对治疗耐药感染的新疗法的医疗需求尚未得到满足。此外，迫切需要有效的治疗方法来解决持续的公共卫生和生物安全问题，即可以对高威胁的精选制剂细菌进行改造，使其对目前所有可用的抗生素产生抗药性。该中心申请的中心假设是，寻找直接针对耐多药革兰氏阳性和革兰氏阴性病原体的新化合物最有可能发现新的抗生素，学术机构和行业之间的协调合作将加快抗生素药物的发现进程。该中心的使命是支持早期药物发现工作，包括靶标验证、化学先导识别、结构-活性关系分析、药代动力学和体内治疗效果，从而开发出适合进行临床前评估的优化化学先导。在AIMS 1和AIMS 2中，我们建议探索针对已被广泛应用的靶标RNA聚合酶和DNA旋转酶的新型化合物；3)表征抗结核分枝杆菌霉酚酸生物合成的新化合物；4)开发未开发的环境衍生新肽，作为新抗生素的来源；以及5)使用计算贝叶斯建模来加速抗菌药物的发现。关键的成功因素是具有创新药物发现计划的项目负责人的力量，以及专注于抗生素开发的生物制药公司Trius Treeutics的加入。该中心由用于化合物优化和进入UMDNJ区域生物遏制实验室进行病原体研究的支持核心的集成基础设施提供支持。整个计划将由David Perlin指导，他是一位经验丰富的翻译研究人员和管理员，由Pharma成员组成的科学咨询委员会，以及一支强大的运营和管理团队，可以有效地管理大型翻译研究项目并促进许可机会。

DESCRIPTION (provided by applicant): An epidemic of multidrug-resistant (MDR) bacterial infections continues to plague global and US health care, and with few new drugs making it to market from a diminished pipeline, there is an unmet medical need for new therapeutics to treat drug-resistant infections. Furthermore, effective therapies are urgently needed to address ongoing public health and biosecurity concerns that high-threat select agent bacteria can be engineered to become resistant to all currently available antibiotics. The central hypotheses of this Center application are that seeking novel compounds directly targeting MDR Gram-positive and Gram-negative pathogens has the greatest probability of finding new antibiotics, and that concerted collaboration among academic institutions and industry will accelerate the antibiotic drug discovery process. The mission of the Center is to support early drug discovery efforts, including target validation, chemical lead identification, structure-activity relationship analysis pharmacokinetics and in vivo therapeutic efficacy, and thereby develop optimized chemical Leads that are suitable candidates for preclinical evaluation. We propose in aims 1 and 2 to explore novel classes of compounds against proven targets with broad spectrum application, RNA polymerase and DNA gyrase; 3) characterize novel compounds against mycolic acid biosynthesis in Mycobacterium tuberculosis; 4) develop untapped environmentally-derived novel peptides, as a source for new antibiotics; and 5) use computational Bayesian modeling to accelerate antibacterial discovery. Critical success factors are the strength of Project Leaders with innovative drug discovery programs, and the inclusion of Trius Therapeutics, a biopharmaceutical company focused on antibiotic development. The Center is supported by an integrated infrastructure of support cores for compound optimization and access to the UMDNJ Regional Biocontainment Lab for pathogen studies. The overall program will be guided by David Perlin, an accomplished translational researcher and administrator, a Scientific Advisory Committee including members of Pharma, and a solid operations and management team that can effectively manage large translational research programs and promote licensing opportunities.