A novel drug retargeting platform for drug-resistant bacterial infections

用于耐药细菌感染的新型药物重靶向平台

• 批准号: 9896464
• 负责人: Felix B Sheinerman
• 金额: $ 29.7万
• 依托单位: TRUDEAU INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-21 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9896464
• 关键词: 3-Dimensional; Address; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Infections; Bioavailable; Biological Assay; Chemicals; Clinical; Clinical Data; Clinical Research; Collection; Coupled; Data; Databases; Development; Dose; Drug Costs; Drug Kinetics; Drug resistance; Elements; Evaluation; Genome; Growth; Human Resources; In Vitro; Infection; Investigation; Lead; Lung; Mammalian Cell; Methods; Microbial Biofilms; Mining; Modeling; Molecular Target; Mycobacterium abscessus; Oral; Pharmaceutical Preparations; Pharmacology; Phenotype; Plasma; Property; Proteome; Resistance development; Resources; SCID Mice; Safety; Series; Shapes; Source; Structure; Surgical Wound Infection; Systems Biology; Testing; Work; acute toxicity; analog; antibiotic resistant infections; bacterial genetics; base; computational chemistry; cytotoxicity test; design; drug action; drug candidate; drug discovery; drug quality; drug testing; efficacy testing; experience; in vitro testing; in vivo; in vivo evaluation; innovation; kinase inhibitor; lead optimization; macrophage; metabolome; metabolomics; mouse model; next generation sequencing; novel; novel therapeutics; pathogen; pathogenic bacteria; pre-clinical; preclinical development; screening; small molecule; tool; transcriptomics; virtual

Abstract Absent new treatment options, bacteria evolve to develop resistance to existing drugs and spread rapidly across the globe. Thus, there is a strong need to identify drugs that: 1) act on bacterial pathogens via novel molecular targets, and 2) are chemically unrelated to clinically used antibiotics. Our innovative approach is designed to meet both of those criteria. Here we propose a novel, general platform to drug discovery that differs from both traditional phenotype- and target-based strategies, and requires a small fraction of the usual costs of drug discovery. Specifically, our proposed drug discovery platform leverages recent advances in bacterial systems biology and builds on large-scale analysis of the mechanisms of action of approved and experimental drugs developed for various indications. Three recent technological advances, coupled with the extensive relevant experience of the key personnel, underlie the proposal: (i) next-generation sequencing, transcriptomic, and metabolomic analyses support precise delineation of the mechanism of action for anti-bacterial drugs; (ii) recent commercial implementation of small molecule shape-comparison methods on GPUs dramatically increase the scale of problems amenable to accurate computational chemistry analysis; and (iii) careful curation of public resources and availability of proprietary databases of approved and experimental drugs enable analysis of large sets of clinical molecules with pre-defined properties. The innovative drug discovery platform proposed herein is designed to identify novel targets, and to discover and develop drugs to treat drug-resistant bacterial infections. In order to establish the feasibility of the approach, we propose to develop drugs working via novel mechanisms of action (MOA) against innately antibiotic-resistant Mycobacterium abscessus.

摘要 如果没有新的治疗选择，细菌会进化成对现有药物产生耐药性， 迅速传遍地球仪。因此，迫切需要鉴定以下药物：1）作用于 细菌病原体通过新的分子靶点，和2）化学上与临床无关 使用抗生素。我们的创新方法旨在满足这两个标准。这里我们 提出了一个新的，通用的平台，以药物发现，不同于传统的表型- 和基于靶点的策略，并且只需要药物发现通常成本的一小部分。 具体来说，我们提出的药物发现平台利用了细菌学的最新进展， 系统生物学，并建立在大规模分析的行动机制，批准 以及针对各种适应症开发的实验性药物。最近的三项技术进步， 加上主要人员的广泛相关经验，这一建议的基础是：㈠ 下一代测序、转录组学和代谢组学分析支持精确的 抗菌药物作用机制的描述;（ii）最近的商业 在GPU上实现小分子形状比较方法显著增加 问题的规模适合准确的计算化学分析;和（iii）仔细 管理公共资源，提供经核准的专有数据库， 实验性药物使得能够分析具有预定义分子的大量临床分子 特性.本文提出的创新药物发现平台旨在识别新的 目标，并发现和开发药物来治疗耐药细菌感染。为了 建立的方法的可行性，我们建议开发药物工作，通过新的 作用机制（MOA）。