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

开发针对多重耐药高威胁细菌制剂的创新疗法的中心

• 批准号: 9923564
• 负责人: David S Perlin
• 金额: $ 663.81万
• 依托单位: HACKENSACK UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923564
• 关键词: Academia; Acinetobacter baumannii; Administrator; Advisory Committees; Anabolism; Animal Model; Antibiotics; Bacterial Infections; Bayesian Modeling; Biotechnology; Cells; Clinical; Communities; Coupled; DNA-Directed RNA Polymerase; Development; Disease Marker; Drug Kinetics; Drug resistance; Drug resistance in tuberculosis; Drug usage; ESKAPE pathogens; Ensure; Enzymes; Epidemic; Evaluation; Gene Cluster; Generations; Gram-Negative Bacteria; Health; Health Care Costs; Healthcare; Histopathology; Hospitals; Immunity; In Vitro; Incentives; Industry; Infection; Infrastructure; Laboratories; Lead; Leadership; Length of Stay; Libraries; Licensing; Lung; Mediating; Medical; Microbial Biofilms; Microbiology; Mining; Modeling; Molecular; Morbidity - disease rate; Multi-Drug Resistance; Multiple Bacterial Drug Resistance; Mycobacterium tuberculosis; Mycolic Acid; O Antigens; Output; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Probability; Property; Pseudomonas aeruginosa; Records; Research Personnel; Resistance; Resistance profile; Resources; Running; Science; Seasons; Serum; Skin Tissue; Soft Tissue Disorder; Solid; Source; Standardization; Structure; Therapeutic; Time; Toxic effect; Toxicology; Translational Research; Vancomycin resistant enterococcus; antimicrobial; base; carbapenem-resistant Enterobacteriaceae; clinically significant; drug action; drug development; drug discovery; enteric pathogen; experience; global health; improved; in vivo; in vivo Model; innovation; methicillin resistant Staphylococcus aureus; mortality; non-tuberculosis mycobacteria; novel; novel drug class; novel strategies; novel therapeutics; operation; pathogen; pre-clinical; preclinical development; process optimization; product development; programs; resistant Klebsiella pneumoniae; screening; small molecule libraries; success; therapeutic target; translational research program; treatment choice

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.

抽象的 多重耐药 (MDR) 细菌感染的流行困扰着美国和全球的医疗保健领域，而且几乎没有 新的药物正在改善但仍然减少的管道中上市，但医疗需求尚未得到满足 寻找治疗临床上重要的高威胁多重耐药感染的新疗法。 包括革兰氏阴性 (GN) 和革兰氏阳性 (GP) ESKAPE 病原体，包括碳青霉烯类耐药性 肠杆菌科 (CRE)、MRSA 和多重耐药和极度耐药结核分枝杆菌 我们的 CETR 假设假设有一个企业型中心。 由世界一流的学术和生物制药研究人员组成，拥有创新和成熟的药物 发现平台专注于临床验证和新颖的目标、有前途的先导和创新 新化合物发现的方法将作为开发选定的优化先导化合物的引擎 针对高威胁 MDR GP 和 GN 细菌的临床前开发候选药物 (PDC) 我们建议： 通过探索针对 RNA 聚合酶的新型化合物，靶向临床上成功的细菌靶标 并分别使用药物“重新定位”作为一种新颖的高成功率药物发现策略 NTM；表征针对结核分枝杆菌酸生物合成关键酶的新型化合物； 利用未开发的环境衍生的新型肽化合物库作为新肽的丰富来源 抗生素，并开发增强血清介导杀伤力的 O 抗原生物合成抑制剂。 方法建立在我们当前成功的 CETR 模型的基础上并对其进行了改进。成功的关键因素包括： 企业式的药物发现/开发方法，项目负责人的实力以及强大的药物 发现计划以及与生物制药的合作伙伴关系，这是成熟药物发现的高度集成矩阵 拥有经验丰富的核心董事、强大的中央领导力和出色的基础设施的支持核心 罗格斯大学区域生物防护实验室的这些组成部分共同构成了一个 CETR 企业。 将通过 PDC 的优化过程简化化合物的发现和进展 通过促进关键的“进行或不进行”决策，整个计划将由一位经验丰富的研究人员指导， 管理员，现任 CETR 药物发现领导者，一个精通药物的科学咨询委员会 开发，以及在大型转化研究方面经验丰富的坚实运营和管理团队 由此产生的知识产权和许可计划用于开发临床产品。