A Scalable Platform to Discover Antimicrobials of Ribosomal Origin

发现核糖体来源抗菌药物的可扩展平台

• 批准号: 10359678
• 负责人: Douglas Alan Mitchell
• 金额: $ 77.02万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-25 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10359678
• 关键词: Actinobacteria class; Address; Analytical Chemistry; Anti-Bacterial Agents; Antibiotics; Antifungal Agents; Bacillus subtilis; Bioinformatics; Biological; Biological Assay; Catalogs; Chemicals; Cloning; Collaborations; Communities; Computer software; Custom; Data; Drug Industry; Drug resistance; Ensure; Escherichia coli; Family member; Firmicutes; Future; Gene Cluster; Genetic; Genome; Goals; Individual; Industrialization; Knowledge; Lasso; Letters; Malaria; Mass Spectrum Analysis; Methods; Mining; Modernization; Modification; Multidimensional NMR Techniques; Names; Natural Product Drug; Natural Products; Pathway interactions; Peptides; Pharmaceutical Preparations; Production; Reporting; Ribosomes; Sampling; Source; Streptomyces; Structure; Therapeutic; Tuberculosis; antimicrobial; base; design; drug discovery; experience; method development; neglected tropical diseases; novel; novel therapeutics; open innovation; pathogenic bacteria; peptide structure; programs; scaffold; scale up; success; synthetic biology; tool

PROJECT SUMMARY/ABSTRACT Natural products have been by far the most prolific source of chemical matter that has been developed into modern antibacterial and antifungal drugs by the pharmaceutical industry. However, despite the pressing need for new drugs to address the alarming rise of drug resistance, especially amongst Gram-negative bacterial pathogens, the rate of discovering natural products has diminished. In this R01 project, we propose to develop a scalable platform to produce novel ribosomal natural products, i.e. ribosomally synthesized and posttranslationally modified peptides (RiPPs). With more than two dozen distinct classes of RiPPs identified thus far, and several new classes being identified each year, RiPPs represent a promising addition to the antibacterial and antifungal drugs biosynthesized by polyketide and non-ribosomal pathways yet they remain vastly underexploited by comparison. Specifically, we will integrate bioinformatics, synthetic biology, and analytical chemistry tools to develop a Fully Automated, Scalable, and high-Throughput (FAST) pipeline for the discovery and characterization of one thousand novel RiPPs from uncharacterized RiPP biosynthetic gene clusters (BGCs) of both known and unknown classes. The resultant novel RiPPs will be assayed for their antibacterial and antifungal activities as well as other related biological activities towards neglected and tropical diseases (tuberculosis and malaria) through a collaboration with Lilly's Open Innovation Drug Discovery Program (openinnovation.lilly.com). This project represents the first large-scale attempt at unlocking the potential of RiPPs as a source of new antibacterial and antifungal drugs, which based on their genetic compactness, are ideally suited for the synthetic biology methods and goals described within. For this project, we propose three interrelated but independently achievable specific aims. Aim 1 will discover novel RiPPs from known classes using lower throughput methods. Aim 2 will scale up the discovery of novel RiPPs from known classes using the FAST pipeline. Aim 3 will predict and produce RiPPs from classes that have not yet been reported, which will ensure a variety of novel natural product scaffolds. Success in the overall project will change the paradigm for natural product discovery and will potentially have a profound impact on the pharmaceutical industry.

项目概要/摘要 天然产物是迄今为止最丰富的化学物质来源，已被开发成 制药工业生产的现代抗菌和抗真菌药物。然而，尽管迫切需要 寻找新药来解决耐药性的惊人上升，特别是革兰氏阴性细菌的耐药性 病原体，发现天然产物的速度已经下降。在这个R01项目中，我们建议开发 生产新型核糖体天然产物的可扩展平台，即核糖体合成和 翻译后修饰肽（RiPP）。由此确定了超过两打不同类别的 RiPP 到目前为止，并且每年都会确定几个新类别，RiPP 代表了抗菌药物的一个有前途的补充 和通过聚酮化合物和非核糖体途径生物合成的抗真菌药物，但它们仍然大量存在 相比之下，开发不足。具体来说，我们将整合生物信息学、合成生物学和分析学 化学工具，用于开发全自动、可扩展和高通量 (FAST) 的发现流程 来自未表征的 RiPP 生物合成基因簇 (BGC) 的 1000 个新型 RiPP 的表征和表征 已知和未知类别。由此产生的新型 RiPP 将进行抗菌和 抗真菌活性以及针对被忽视的热带疾病的其他相关生物活性 （结核病和疟疾）通过与礼来公司的开放创新药物发现计划合作 （openinnovation.lilly.com）。该项目是释放 RiPP 潜力的首次大规模尝试 作为新型抗菌和抗真菌药物的来源，其基于其遗传紧凑性，是理想的选择 适合其中描述的合成生物学方法和目标。对于这个项目，我们提出了三个建议 相互关联但可独立实现的具体目标。目标 1 将从已知类别中发现新的 RiPP 使用较低吞吐量的方法。目标 2 将利用以下方法从已知类别中扩大新型 RiPP 的发现 快速管道。目标 3 将从尚未报告的类别中预测并生成 RiPP，这将 确保各种新颖的天然产物支架。整个项目的成功将改变范式 天然产物的发现可能会对制药行业产生深远的影响。