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 对微生物基因组内天然产物产生基因簇的估计还远远不够。 大于已知天然产物的数量，表明存在大量未开发的分子 不幸的是，这些生物体具有作为新药物的巨大潜力。 天然产物发现的范式不适合获取这种丰富的分子，提供了 因此，在现代时代这是不可接受的。 微生物提供新的天然产品和我们有效利用这种潜力的能力。 为了弥补这一差距，微生物制药公司正在开发下一代技术，该技术将提供无与伦比的 获取这些化合物以及表征和使用它们的方法。 Microbial Pharmaceuticals 的长期目标是提供完整的二级路线图 放线菌内的新陈代谢——已知能产生最多数量的天然产物——通过进行 对 10,000 种不同菌株进行代谢基因组筛选，此过程生成的数据将提供所有信息。 表达的代谢物及其耦合的生物合成基因簇，而这种大规模的努力将 克服了仅研究少数菌株的方法所面临的“神秘”基因簇问题。 Microbial Pharmaceuticals 将优化我们的代谢基因组学数据采集平台（目标 1）和 同时改进我们的相关算法（目标 2）。 使用 UPLC 和高精度质谱法可实现可重复的数据采集 降低成本和提高采购率的目标（目标 1a）将在 50 上进行试点。 新的细菌菌株以及纳入已知和新天然产物数据库的数据（目标 1b）。 第一阶段目标 1 的成功成果将为实现我们的长期目标奠定重要基础 未来目标是廉价且高效地筛选 10,000 株菌株，我们还将实施 MS2 网络。 将特征纳入代谢基因组数据库（目标 2）。 所研究的 50 个菌株的代谢基因组数据的组合，加上改进的 相关性，将提供大量可以以确定性方式访问的新分子。 以全新的运作方式运作，将会出现源源不断的高价值化合物， 它们经过大自然数千年的磨练，在复杂的生物系统中发挥作用。