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

摘要 一种流行的多药耐药(MDR)细菌感染困扰着美国和全球医疗保健，而且几乎没有人 新药从不断改善但仍在减少的流水线推向市场，还有一个未得到满足的医疗需求 用于治疗临床上重要的高威胁多药耐药感染的新疗法。高威胁特工 包括革兰氏阴性(GN)和革兰氏阳性(GP)ESKAPE病原体，包括碳青霉烯耐药 肠杆菌科(CRE)、耐甲氧西林金黄色葡萄球菌(MRSA)与多重耐药和极耐药结核分枝杆菌 和非结核分枝杆菌(NTM)。我们的CETR假设假设一个企业式的中心 由世界级学术和生物制药研究人员组成，拥有创新和成熟的药物 发现平台专注于经过临床验证的新靶点、有希望的线索和创新 新化合物发现的方法将作为引擎，开发选定的优化线索和 针对高威胁的MDR、GP和GN细菌的临床前开发候选者(PDC)。我们建议： 探索新型抗RNA聚合酶化合物靶向临床成功的细菌靶点 并分别使用药物重新定位作为一种新的高概率成功的药物发现策略来对抗 抗结核分枝杆菌霉酚酸生物合成关键酶的新化合物的特征； 利用未开发的环境衍生新型多肽化合物文库作为新的 抗生素，并开发O抗原生物合成抑制剂，以加强血清介导的杀伤。我们的 该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，用强大的药物增强项目负责人的力量 发现计划和与生物制药的合作伙伴关系，生物制药是成熟药物发现的高度整合的矩阵 支持具有经验丰富的核心总监、强大的中央领导力和卓越的基础设施的核心 罗格斯地区生物遏制实验室。这些组件共同组成了CETR企业，该企业 将通过向PDC的优化过程来简化化合物的发现和进展 通过促进关键的“去，不去”的决定。整个项目将由一位有成就的研究人员指导， 署长，现任CETR药物发现负责人，一个精通药物的科学咨询委员会 开发，以及在大型翻译研究方面经验丰富的坚实的运营和管理团队 导致知识产权和许可的计划，以开发临床产品。

Abstract 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; exploit untapped environmentally-derived novel peptidic compound libraries as a rich source for new antibiotics, and develop O-antigen biosynthetic inhibitory agents that potentiate serum-mediated killing. 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.