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：
10394984
负责人：
David S Perlin
金额：
$ 663.83万
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/10394984
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 resistant Mycobacteria 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 Medical Microbial Biofilms Microbiology Mining Modeling Molecular Morbidity - disease rate Multi-Drug Resistance Multiple Bacterial Drug Resistance Mycobacterium tuberculosis Mycolic Acid Output Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Pharmacology Phase Probability Property Pseudomonas aeruginosa Records Research Personnel Resistance 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

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.

多种抗药性（MDR）细菌感染的流行困扰着我们和全球医疗保健，很少有新药因改善但仍减少的管道而推向市场，因此对新疗法的需求不足，可以治疗临床上重要的高威胁性多重耐药性感染。高威胁性药物包括革兰氏阴性（GN）和革兰氏阳性（GP）Eskape病原体，包括抗碳青霉烯型肠杆菌科（CRE），MRSA和多药和极度耐药的结核病和无抗性结核病和非耐药性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.我们建议：通过探索针对RNA聚合酶的新型化合物，并分别将药物“重新定位”用作针对NTMS的新型高概率的药物发现策略，靶向临床成功的细菌靶标。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；并利用未开发的环境衍生的新型肽化合物库作为新抗生素的丰富来源。我们的方法基于并完善了我们当前成功的Cetr模型。成功的关键因素包括企业风格的药物发现/开发方法，具有强大的药物发现计划的项目领导者的力量以及与Biopharma的伙伴关系，Biopharma是一个高度综合的成熟药物发现支持核心，与经验丰富的核心导演，强大的中心领导以及与Rutgers的基础设施与Rutgers区域生物构成实验室。总的来说，这些组件包括一个Cetr企业，该企业将通过促进关键的“ GO GO，无需”决策，通过优化过程来简化化合物的发现和进步。整个计划将由有成就的研究人员，管理员和现任药物发现的CORTH领导者进行指导，该咨询委员会是一个熟悉药物开发的科学咨询委员会，以及在大型翻译研究计划中经验丰富的坚实的运营和管理团队，从而获得IP和许可以开发临床产品。