Center to develop therapeutic countermeasures to high-threat bacterial agents

描述（由申请人提供）：耐多药（MDR）细菌感染的流行继续困扰着全球和美国的卫生保健，并且很少有新药从减少的管道中进入市场，因此对治疗耐药感染的新疗法的医疗需求未得到满足。此外，迫切需要有效的治疗方法来解决持续存在的公共卫生和生物安全问题，即高威胁选择细菌可以被改造成对所有现有抗生素具有耐药性。本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，并且学术机构和工业界之间的协调合作将加速抗生素药物的发现过程。该中心的使命是支持早期药物发现工作，包括靶点验证、化学先导物鉴定、构效关系分析、药代动力学和体内治疗效果，从而开发出适合临床前评估的优化化学先导物。我们在目标1和目标2中提出，探索具有广谱应用的针对已证实靶点的新型化合物，RNA聚合酶和DNA回转酶；3)鉴定抗结核分枝杆菌菌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；5)利用计算贝叶斯模型加速抗菌药物的发现。关键的成功因素是项目领导者在创新药物发现项目方面的实力，以及Trius Therapeutics（一家专注于抗生素开发的生物制药公司）的加入。该中心由化合物优化支持核心的综合基础设施提供支持，并可进入UMDNJ区域生物控制实验室进行病原体研究。整个项目将由David Perlin（一位有成就的转化研究人员和管理者）、一个包括制药公司成员在内的科学咨询委员会以及一个可靠的运营和管理团队指导，该团队可以有效地管理大型转化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.