Center to develop innovative therapeutics to multidrug resistant high-threat bacterial agents

耐多药（MDR）细菌感染的流行困扰着美国和全球的卫生保健，由于很少有新药能够从不断改善但仍然减少的管道中进入市场，因此对治疗临床上重要的高威胁耐多药感染的新疗法的医疗需求尚未得到满足。高威胁病原体包括革兰氏阴性（GN）和革兰氏阳性（GP） ESKAPE病原体，包括耐碳青霉烯类肠杆菌科（CRE）， MRSA以及多药和极耐药结核分枝杆菌和非结核分枝杆菌（NTM）。我们的CETR假设假设，一个由世界级学术和生物制药研究人员组成的企业级中心，拥有创新和完善的药物发现平台，专注于临床验证的新靶点、有前途的先导物和新化合物发现的创新方法，将作为开发选定的优化先导物和临床前开发候选物（PDCs）的引擎，针对高威胁MDR GP和GN细菌。我们建议：通过探索针对RNA聚合酶的新型化合物来靶向临床成功的细菌靶点，并单独使用药物“重新定位”作为一种新的高概率成功的针对ntm的药物发现策略；鉴定抗结核分枝杆菌真菌酸合成关键酶的新化合物；利用尚未开发的环境衍生的新型肽类化合物文库作为新抗生素的丰富来源。我们的方法建立并改进了我们目前成功的ctr模型。成功的关键因素包括企业式的药物发现/开发方法，项目领导者的力量，强大的药物发现计划和与生物制药的合作伙伴关系，高度集成的成熟药物发现支持核心矩阵，经验丰富的核心董事，强大的中央领导，以及罗格斯大学区域生物控制实验室的出色基础设施。总的来说，这些组件组成了一个ctr企业，通过促进关键的“进行或不进行”决策，通过优化过程，将化合物的发现和进步流程化。整个项目将由一位有成就的研究人员、管理人员和目前ctr药物发现领域的领导者、一个精通药物开发的科学咨询委员会、以及一支在大型转化研究项目中具有丰富经验的运营和管理团队指导，这些项目导致了知识产权和临床产品的许可开发。

An epidemic of multidrug-resistant (MDR) bacterial infections plagues US and global health care, and with few new drugs making it to market from an improving but still diminished pipeline, there is an unmet medical need for new therapeutics to treat clinically important high-threat multidrug-resistant infections. High-threat agents comprise Gram negative (GN) and Gram positive (GP) ESKAPE pathogens including Carbapenem-resistant Enterobacteriaceae (CRE), MRSA and multidrug- and extremely drug-resistant Mycobacterium tuberculosis and nontuberculous Mycobacteria (NTM). Our CETR hypothesis postulates that an enterprise-style Center comprised of world-class academic and biopharma investigators with innovative and well-established drug discovery platforms focused on clinically validated and novel targets, promising Leads, and innovative approaches for new compound discovery will serve as an engine to develop selected optimized Leads and Preclinical Development Candidates (PDCs) against high-threat MDR GP and GN bacteria. We propose to: target clinically-successful bacterial targets by exploring novel classes of compounds against RNA polymerase and separately use drug 'repositioning' as a novel high-probability-to-succeed drug discovery strategy against NTMs; characterize novel compounds against key enzymes of mycolic acid biosynthesis in M. tuberculosis; and exploit untapped environmentally-derived novel peptidic compound libraries as a rich source for new antibiotics. Our approach builds upon and refines our current successful CETR model. Critical factors for success include the enterprise-style approach to drug discovery/development, the strength of Project Leaders with robust drug discovery programs and partnerships with biopharma, a highly integrated matrix of mature drug discovery support cores with experienced Core directors, strong central leadership, and outstanding infrastructure with the Rutgers Regional Biocontainment Lab. Collectively, these components comprise a CETR enterprise that will streamline the discovery and advancement of compounds through the optimization process toward PDCs by facilitating critical "go, no-go" decisions. The overall program will be guided by an accomplished researcher, administrator, and current CETR leader in drug discovery, a Scientific Advisory Committee well versed in drug development, and a solid operations and management team that is experienced in large translational research programs resulting in IP and licensing to develop clinical products.