New Methodologies for Accelerating Natural Product Discovery

加速天然产品发现的新方法

• 批准号: 8888885
• 负责人: BRIAN O BACHMANN
• 金额: $ 36.9万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-15 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8888885
• 关键词: Actinobacteria class; Address; Antibiotic Resistance; Antibiotics; Aptitude; Architecture; Atlases; Bioinformatics; Biological; Biological Factors; Biostatistical Methods; Chemicals; Clinic; Complex; Correlation Studies; Crude Extracts; Data; Data Set; Detection; Drug usage; Eating; Ecology; Ecosystem; Environment; Expeditions; Future; Gene Cluster; Gene Expression Profile; Genetic; Genetic Transcription; Genome; Genome Scan; Genomics; Genotype; Goals; Gold; Health; Human; In Situ; Libraries; Life; Link; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Medicine; Metabolic; Metabolic Activation; Metabolism; Metagenomics; Methodology; Methods; Microbe; Mining; Molecular; Natural Product Drug; Neurodegenerative Disorders; Operon; Organism; Patients; Pharmaceutical Preparations; Pharmacopoeias; Process; Regulation; Research; Research Personnel; Resistance; Resolution; Resources; Role; Sampling; Source; Stimulus; Surface; Surveys; Techniques; Technology; Testing; Time; Translations; Tube; Work; analytical method; base; cohort; comparative; data mining; drug candidate; drug development; drug discovery; exhaust; follow-up; genome sequencing; global health; human disease; insight; instrument; interest; ion mobility; metabolomics; microbial; microbiome; microorganism; novel therapeutics; public health relevance; pyrosequencing; tool

 DESCRIPTION (provided by applicant): Secondary metabolites are the origin of a large fraction of drugs used to successfully treat life threatening-illnesses. Because secondary metabolites, their derivatives, or compounds inspired by them are so widespread in the clinic, there remains great enthusiasm for their continued discovery. However, enthusiasm for the work of secondary metabolite discovery has waned because after decades of mining our environment for drug candidates, easily accessible ecosystems have been exhausted, and the methods for discovery currently employed are extremely labor intensive, with a low per-organism compound yield, and the revelation of new chemical diversity has apparently slowed down. However, the recent advent of inexpensive genome sequencing technology has demonstrated unambiguously that efforts to date only scratch the surface of the available natural chemical diversity. Whereas most organisms have generally yielded one or two natural products, genomics has informed us that these same organisms contain the genetic blueprints for many more - ten or twenty times more. But to date few if any facile generalizable methods for eliciting the translation of these blueprints into molecules in tubes have been provided. Herein we tackle two major objectives of opening new ecosystems to natural product discovery and removing the expression bottleneck to accelerate natural product discovery in microorganisms from unusual sources. To accomplish these goals we develop new instrumental, analytical, bioinformatics, and biostatistical methods to capture the information in a comprehensive microbial metabolome that is relevant to new compound discovery and chemical ecology. Our three aims in support of these objectives encompass three major specific aims which are (1) Chemical biogeological survey of secondary metabolism in hypogean (cave) ecosystems, (2) to develop native metabolic activation of biosynthetic processes for discovery, (3) provide an atlas of stimulus to genotype for rational selection of chemical and biological conditions that induce secondary metabolism in organisms with high apparent biosynthetic aptitude. The successful completion of the proposed research is highly relevant to human health because it will provide methods to accelerate the identification of natural products which have had and continue to have a large impact on human health. Furthermore, the discovery of the mode of action of newly discovered and rediscovered compounds for which mode of action has yet to be determined may provide new therapeutics.

 描述(申请人提供)：次生代谢物是用于成功治疗危及生命的疾病的很大一部分药物的来源。由于次生代谢物、它们的衍生物或由它们激发的化合物在临床上如此广泛，人们仍然对它们的继续发现抱有极大的热情。然而，人们对次生代谢物发现工作的热情已经消退，因为经过几十年对候选药物环境的挖掘，容易到达的生态系统已经耗尽，目前使用的发现方法劳动密集型，每个有机体的化合物产量很低，新的化学多样性的揭示显然已经放缓。然而，最近廉价的基因组测序技术的出现明确地表明，迄今为止的努力只是触及了可用自然化学多样性的表面。虽然大多数生物体通常只产生一到两种天然产物，但基因组学告诉我们，这些相同的生物体包含更多的基因蓝图--十倍或二十倍以上。但到目前为止，几乎没有提供任何简单、通用的方法来将这些蓝图转化为试管中的分子。在这里，我们解决了两个主要目标：为天然产物发现打开新的生态系统，以及消除表达瓶颈，以加速从不寻常来源的微生物中发现天然产物。为了实现这些目标，我们开发了新的仪器、分析、生物信息学和生物统计学方法，以捕获与新化合物发现和化学生态相关的综合微生物代谢组中的信息。我们支持这些目标的三个目标包括三个主要的具体目标：(1)海底(CAVE)生态系统次生代谢的化学生物地理学调查，(2)开发生物合成过程的天然代谢激活以供发现，(3)为合理选择诱导具有高表观生物合成能力的生物体的次生代谢的化学和生物条件提供一个基因刺激图谱。这项拟议研究的成功完成与人类健康高度相关，因为它将提供方法，加速确定对人类健康已经并将继续产生重大影响的天然产品。此外，新发现和重新发现的化合物的作用模式的发现可能提供新的治疗方法。