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.

抽象的 没有新的治疗选择，细菌会发展出对现有药物的抗性和 迅速传播到全球。因此，迫切需要识别：1）采取行动 通过新分子靶标的细菌病原体，2）在化学上与临床无关 使用的抗生素。我们的创新方法旨在满足这两个标准。我们在这里 提出了一个新颖的药物发现平台，与传统的表型不同 - 和基于目标的策略，需要一小部分药物发现成本。 具体而言，我们提议的药物发现平台利用细菌的最新进展 系统生物学并以大规模分析对批准的作用机理进行大规模分析 以及用于各种适应症的实验药物。最近的三个技术进步， 再加上关键人员的广泛相关经验，这是提案的基础：（i） 下一代测序，转录组和代谢组分析支持精确 描述抗菌药物的作用机理； （ii）最近的广告 在GPU上实施小分子形状比较方法急剧增加 问题的规模适用于准确的计算化学分析； （iii）小心 公共资源的策划和批准的专有数据库的可用性 实验药物可以分析具有预定义的大量临床分子 特性。本文提出的创新药物发现平台旨在识别新颖 靶标，并发现和开发药物以治疗耐药细菌感染。为了 确定方法的可行性，我们建议开发通过新颖的药物 作用机理（MOA）针对天生抗生素抗生素的分枝杆菌。