A Metabologenomics Platform for Large-Scale, High-Throughput Natural Product Discovery

用于大规模、高通量天然产物发现的代谢基因组学平台

• 批准号: 9255526
• 负责人: Anthony Whitney Goering
• 金额: $ 15万
• 依托单位: MICROBIAL PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9255526
• 关键词: Actinobacteria class; Actinomyces Infections; Algorithms; Bacteria; Bioinformatics; Biotechnology; Chemicals; Communities; Complex; Country; Coupled; Data; Databases; Development; Family; Future; Gene Cluster; Genome; Genomics; Goals; Harvest; Industry; Infusion procedures; Maps; Mass Spectrum Analysis; Medicine; Metabolism; Methods; Modernization; Modus; Molecular; Natural Products; Nature; Organism; Outcome; Pharmacognosy; Pharmacologic Substance; Phase; Positioning Attribute; Process; Public Health; Reproducibility; Research; Resources; Small Business Innovation Research Grant; Source; Stream; Technology; complex biological systems; cost; data acquisition; human disease; improved; innovation; interest; metabolome; metabolomics; microbial; microorganism; new technology; next generation; novel; scaffold; screening; tool

ABSTRACT The estimates of natural product producing gene clusters within the genomes of microorganisms are far greater than the number of known natural products, indicating that there is a wealth of untapped molecules within these organisms that offer huge potential as leads for new medicines. Unfortunately, the prevailing paradigms for natural product discovery are ill suited for accessing this bounty of molecules, providing a rate of discovery that is unacceptable in the modern era. There is, therefore, a significant gap between the potential of microorganisms to deliver new natural products and our ability to access this potential effectively. To bridge this gap, Microbial Pharmaceuticals is developing the next-generation technology that will deliver unparalleled access to these compounds and the means by which they can be characterized and put to use. The long-term goal of Microbial Pharmaceuticals is to provide a complete roadmap of secondary metabolism within actinobacteria—known to produce the greatest numbers of natural products—by conducting metabologenomic screening of 10,000 different strains. The data generated from this process will provide all expressed metabolites and their coupled biosynthetic gene clusters, while the large scale of this effort will overcome the “cryptic” gene cluster problem faced by approaches that only investigate a few strains. Microbial Pharmaceuticals will optimize our metabologenomics data acquisition platform (Aim 1) and simultaneously improve upon our correlation algorithms (Aim 2). Optimization of the platform to allow rapid and reproducible data acquisition will be achieved using UPLC and high-mass accuracy mass spectrometry with the goal of decreasing cost and increasing the rate of acquisition (Aim 1a). This process will be piloted on 50 new bacterial strains and the data incorporated into a database of known and new natural products (Aim 1b). The successful outcome of Aim 1 during Phase I will lay the significant groundwork to achieve our long-term future goal of screening 10,000 strains cheaply and efficiently. We will also implement an MS2 networking feature into the metabologenomics database (Aim 2). The combination of metabologenomic data from the 50 strains investigated, coupled to the improved correlations, will provide a plethora of new molecules that may be accessed in a deterministic fashion. By operating in a fundamentally new modus operandi, a steady stream of high value compounds will emerge, which have been honed by nature over millennia for activity in complex biological systems.

抽象的 微生物基因组内的天然产物产生基因簇的估计值很远 大于已知天然产品的数量，表明有大量未开发的分子 在这些生物体中，作为新药物的铅具有巨大潜力。不幸的是，盛行 天然产品发现范例不适合获取这一分子的赏金，提供了速度 在现代时代不可接受的发现。因此，在潜力之间存在很大的差距 微生物提供新的天然产品和我们有效获取这种潜力的能力。桥接 这种差距，微生物药品正在开发下一代技术，该技术将提供无与伦比的 访问这些化合物以及它们可以表征和使用的手段。 微生物药物的长期目标是提供次要的完整路线图 肌动杆菌内的代谢（已知会产生大量天然产物）的代谢。 10,000种不同菌株的Metablenomic筛查。从此过程产生的数据将提供全部 表达的代谢产物及其耦合的生物合成基因簇，而大规模的努力将 克服仅研究一些菌株的方法所面临的“隐秘”基因簇问题。 微生物药物将优化我们的Metablogenomics数据采集平台（AIM 1）和 简单地改善了我们的相关算法（AIM 2）。平台的优化以允许快速和 使用UPLC和高质量精度质谱法可以实现可再现的数据采集 降低成本并提高采集率的目标（AIM 1A）。这个过程将在50中试用 新的细菌菌株以及已纳入已知和新天然产品数据库的数据（AIM 1B）。 AIM 1在阶段I的成功结果将奠定重要的基础，以实现我们的长期 廉价且有效筛查10,000株的未来目标。我们还将实施MS2网络 特征进入Metablogenomics数据库（AIM 2）。 来自研究的50个菌株的元基因组数据的组合，耦合到改进 相关性将提供大量可能以确定性方式访问的新分子。经过 在从根本上进行新的作案手术中运行，将出现稳定的高价值化合物流， 几千年来，这在复杂的生物系统中都受到了自然的尊重。