A novel drug retargeting platform for drug-resistant bacterial infections

摘要 如果没有新的治疗选择，细菌就会进化成对现有药物和 在全球范围内迅速传播。因此，迫切需要识别以下药物：1)起作用 细菌病原体通过新的分子靶点，以及2)化学上与临床无关 使用了抗生素。我们的创新方法旨在满足这两个标准。在这里我们 提出一个新颖的、通用的药物发现平台，既不同于传统的表型，也不同于 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。 具体地说，我们提出的药物发现平台利用了细菌领域的最新进展 系统生物学，并建立在大规模分析批准的作用机制的基础上 以及为各种适应症开发的实验药物。三项最新的技术进步， 加上主要人员的丰富相关经验，这项建议的基础是：(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制；(Ii)最近商业化 小分子形状比较法在图形处理器上的实现显著增加 适用于精确计算化学分析的问题的规模；以及(Iii)仔细 管理公共资源和提供已核准和可用的专有数据库 实验药物能够分析具有预定义的大组临床分子 属性。本文提出的创新药物发现平台旨在识别新的 目标，并发现和开发治疗耐药细菌感染的药物。为了 建立这种方法的可行性，我们建议通过创新的方式开发药物 抗天生耐药脓肿分支杆菌的作用机制(MOA)。

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.