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: 10613883
• 负责人: David S Perlin
• 金额: $ 652.13万
• 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/10613883
• 关键词: Academia; Acceleration; Acinetobacter baumannii; Administrator; Advisory Committees; Anabolism; Animal Model; Antibiotics; Bacterial Infections; Bacteriocides; Bayesian Modeling; Biological; 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; Environment; 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; Marketing; Medical; Microbial Biofilms; Mining; Modeling; Molecular; Morbidity - disease rate; Multi-Drug Resistance; Multiple Bacterial Drug Resistance; Mycobacterium tuberculosis; Mycolic Acid; Output; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Positioning Attribute; Predisposition; 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; Vancomycin-resistant S. aureus; antimicrobial; 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; pharmacologic; pre-clinical; preclinical development; process optimization; product development; programs; resistant Klebsiella pneumoniae; screening; small molecule libraries; success; therapeutic target; translational research program; treatment choice

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.

多药耐药（MDR）细菌感染的流行病困扰着美国和全球医疗保健，并且很少有新药从改善但仍然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存在未满足的医疗需求。高威胁病原体包括革兰氏阴性（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）、MRSA以及多重耐药和极端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，一个由世界一流的学术和生物制药研究人员组成的企业式中心，拥有创新和完善的药物发现平台，专注于临床验证和新型靶标，有前途的先导化合物和新化合物发现的创新方法，将作为开发针对高威胁MDR GP和GN细菌的选定优化先导化合物和临床前开发候选化合物（PDC）的引擎。我们建议：通过探索针对RNA聚合酶新型化合物和单独使用药物“重新定位”作为针对NTM的新型高成功概率药物发现策略，靶向临床成功的细菌靶标;结核病;并开发未开发的环境衍生的新肽化合物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、具有强大药物发现计划和与生物制药合作伙伴关系的项目领导者的实力、高度集成的成熟药物发现支持核心矩阵以及经验丰富的核心董事、强有力的中央领导以及罗格斯大学区域生物防护实验室的出色基础设施。总的来说，这些组件组成了一个CETR企业，该企业将通过促进关键的“去，不去”决策，通过对PDC的优化过程来简化化合物的发现和进步。整个计划将由一位有成就的研究人员，管理员和目前CETR在药物发现方面的领导者，一个精通药物开发的科学咨询委员会以及一个在大型转化研究计划中经验丰富的坚实的运营和管理团队指导，从而获得IP和许可以开发临床产品。

项目成果

Mycobacterium tuberculosis KasA as a drug target: Structure-based inhibitor design.

• DOI: 10.3389/fcimb.2022.1008213
• 发表时间: 2022
• 期刊: Frontiers in cellular and infection microbiology
• 影响因子: 5.7