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.

多重耐药 (MDR) 细菌感染的流行困扰着美国和全球的医疗保健，而且几乎没有新药从不断改善但仍然减少的管道中推向市场，因此对治疗临床上重要的高威胁多重耐药感染的新疗法的医疗需求尚未得到满足。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，包括碳青霉烯类耐药肠杆菌 (CRE)、MRSA 以及多重耐药和极度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颖的靶点、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 细菌的精选优化先导化合物和临床前开发候选物 (PDC) 的引擎。我们建议：通过探索针对 RNA 聚合酶的新型化合物来瞄准临床上成功的细菌靶标，并单独使用药物“重新定位”作为针对 NTM 的新型高成功率药物发现策略；表征针对结核分枝杆菌酸生物合成关键酶的新型化合物；并利用未开发的环境衍生新型肽化合物库作为新型抗生素的丰富来源。我们的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、项目领导者的实力、强大的药物发现计划以及与生物制药的合作伙伴关系、由经验丰富的核心董事组成的成熟药物发现支持核心的高度集成矩阵、强大的中央领导力以及罗格斯地区生物防护实验室的出色基础设施。总的来说，这些组件构成了一个 CETR 企业，该企业将通过促进关键的“进行、不进行”决策，通过针对 PDC 的优化过程来简化化合物的发现和开发。整个计划将由一位卓有成就的研究员、管理人员和当前 CETR 药物发现领导者、精通药物开发的科学咨询委员会以及在大型转化研究项目中经验丰富的运营和管理团队指导，从而获得知识产权和开发临床产品的许可。

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