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

多药耐药(MDR)细菌感染的流行困扰着美国和全球医疗保健，由于几乎没有新药从正在改善但仍在减少的管道中进入市场，对治疗临床上重要的高威胁多药耐药感染的新疗法的医疗需求尚未得到满足。高危因素包括革兰氏阴性(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)、耐甲氧西林金黄色葡萄球菌(MRSA)和多重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式中心，拥有创新和成熟的药物发现平台，专注于临床验证和新的靶点、有希望的线索和新化合物发现的创新方法，将成为开发选定的优化线索和临床前开发候选对象(PDC)的引擎，以对抗高威胁的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上成功的细菌靶点，并分别使用药物重新定位作为针对非结核分枝杆菌的新的高概率成功的药物发现策略；表征针对结核分枝杆菌霉酚酸生物合成关键酶的新化合物；以及开发未开发的环境衍生的新型多肽化合物文库作为新抗生素的丰富来源。我们的方法建立在我们目前成功的CETR模式的基础上并加以完善。成功的关键因素包括企业式的药物发现/开发方法、具有强大药物发现计划的项目负责人的实力以及与生物制药公司的合作伙伴关系、由经验丰富的核心董事组成的成熟药物发现支持核心的高度整合矩阵、强大的中央领导以及罗格斯地区生物遏制实验室的出色基础设施。总体而言，这些组件组成了一家CETR企业，该企业将通过促进关键的“通过、不通过”决策，通过对PDC的优化过程来简化化合物的发现和进展。整个计划将由一位在药物发现方面经验丰富的研究人员、行政人员和CETRR现任领导人指导，一个精通药物开发的科学咨询委员会，以及一支在大型翻译研究项目中经验丰富的运营和管理团队，这些项目导致开发临床产品的知识产权和许可。

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.