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.

项目摘要/摘要 天然产品是迄今为止最多产的化学物质来源 制药行业的现代抗菌和抗真菌药物。但是，尽管需要 为了解决新药以解决耐药性的令人震惊的升高，尤其是在革兰氏阴性细菌中 病原体，发现天然产品的速度降低了。在这个R01项目中，我们建议开发 一个可扩展的平台，用于生产新型核糖体天然产物，即核糖体合成和 翻译后修饰的肽（RIPP）。鉴定有二十多个不同类别的RIPP类 远处，每年都确定几个新课程，Ripps代表了抗菌的有希望的补充 以及通过聚酮化合物和非核糖体途径生物合成的抗真菌药物，但它们仍然很大 通过比较不忽视。具体而言，我们将整合生物信息学，合成生物学和分析 化学工具以开发全自动，可扩展和高通量（快速）管道的化学工具 以及来自未表征的RIPP生物合成基因簇（BGC）的一千个新型河流的表征 已知和未知类别。由此产生的小说河流将用于其抗菌和 抗真菌活动以及其他相关的生物学活动，用于被忽视和热带疾病 （结核病和疟疾）通过与礼来开放创新药物发现计划的合作 （openinnovation.lilly.com）。该项目代表了解锁河流潜力的首次大规模尝试 作为新的抗菌药物和抗真菌药物的来源，基于其遗传紧缩，是理想情况下 适合内部描述的合成生物学方法和目标。对于这个项目，我们建议三个 相互关联但独立实现的特定目的。 AIM 1将发现已知班级的新颖河流 使用较低的吞吐量方法。 AIM 2将使用The已知班级发现新颖的Ripps的发现 快速管道。 AIM 3将预测并产生尚未报告的课程的裂痕，这将 确保各种新型的天然产品脚手架。整个项目的成功将改变 天然产品发现，并有可能对制药行业产生深远的影响。