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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的多种耐药（MDR）细菌感染的流行病困扰着我们和全球医疗保健，很少新药通过改善但仍减少的管道来推向市场，有未满足的医疗需求用于治疗临床上重要的高威胁性多药物感染的新疗法。高威胁代理商包括革兰氏阴性（GN）和革兰氏阳性（GP）Eskape病原体，包括抗碳青霉烯肠杆菌科（CRE），MRSA和多药耐药性结核分枝杆菌和非结核分枝杆菌（NTM）。我们的CTR假设假设企业风格中心通过创新且建立良好的药物完成了世界一流的学术和生物制药研究人员发现平台着重于临床验证和新颖的目标，有前途的潜在客户和创新的目标新的复合发现方法将作为开发选定优化的潜在客户的引擎针对高威胁性MDR GP和GN细菌的临床前发展候选者（PDC）。我们建议：通过探索针对RNA聚合酶的新型化合物，靶向临床成功的细菌靶标并单独使用“重新定位”药物作为一种新型的高概率，以实现的药物发现策略 ntms;针对结核分枝杆菌中麦芽酸生物合成的关键酶来表征新颖的化合物；利用未开发的环境衍生的新型肽化合物库作为新的抗生素，并形成潜在的血清介导的杀伤的O-抗原生物合成抑制剂。我们的方法基于并完善了我们当前成功的CERTR模型。成功的关键因素包括企业风格的药物发现/开发方法，强大的药物项目领导者的实力发现计划和与Biopharma的伙伴关系，这是一个高度整合的成熟药物发现的矩阵支持经验丰富的核心主管，强大的中央领导和出色的基础设施的支持核心 Rutgers区域生物膜维护实验室。总的来说，这些组件包括一个Cetr企业将通过优化过程简化化合物的发现和进步通过促进批判的“无关，无行为”的决定。整个计划将由有成就的研究人员指导管理员和现任药物发现领导者，一个科学咨询委员会精通毒品开发以及在大型翻译研究中经验丰富的坚实运营和管理团队导致IP和许可的程序开发临床产品。