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（由适用提供）：二级代谢产物是用于成功治疗生命威胁性易变的大量药物的起源。由于次要代谢产物，其衍生物或受其启发的化合物在诊所中如此普遍，因此对他们的持续发现仍然非常热情。但是，对第二代代谢物发现的工作的热情已经减弱，因为经过数十年的挖掘我们的候选毒品环境，易于获得的生态系统已经耗尽，目前采用的发现方法非常强，劳动力强度极高，人均复合产量低，而新的化学多样性的启示显然很慢。但是，廉价基因组测序技术的最近进步表明，迄今为止的努力仅刮擦了可用的自然化学多样性的表面。尽管大多数生物通常产生了一种或两种天然产物，但基因组学告诉我们，这些相同的生物包含遗传蓝图，多十或二十倍。但是迄今为止，很少有人提供了将这些蓝图转换为试管中分子的任何可容易的推广方法。本文中，我们解决了开放新生态系统以发现自然产品发现的两个主要目标，并删除了表达瓶颈，以加速来自异常来源的微生物的天然产品发现。为了实现这些目标，我们开发了新的工具，分析，生物信息学和生物统计学方法，以在与新的复合发现和化学生态学相关的全面微生物代谢组中捕获信息。我们的三个目标是支持这些目标的三个主要特定目的，即（1）降低（洞穴）生态系统中次生代谢的化学生物地质研究，（2）为发现生物合成过程的天然代谢激活，（2）用于发现的生物合成过程，（3）刺激了刺激的刺激态度和生物学选择，以实现化学态度，以构想具有合理的构想，以构想有合理的生物学，以构想有合理的生物学，以构想有合理的生物学，以构想有合理的生物学症状。生物合成能力。拟议研究的成功完成与人类健康高度相关，因为它将提供加速鉴定自然产品并继续对人类健康产生重大影响的方法。此外，发现新发现和重新发现的化合物的作用方式的发现可能会提供新的疗法。