New Methodologies for Accelerating Natural Product Discovery

加速天然产品发现的新方法

基本信息

批准号：
9421557
负责人：
BRIAN O BACHMANN
金额：
$ 39.2万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-15 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9421557
关键词：
Actinobacteria class Address Anabolism Antibiotic Resistance Antibiotics Aptitude Architecture Atlases Bioinformatics Biological Biostatistical Methods Chemicals Clinic Clinical Complex Correlation Studies Crude Extracts Data Data Set Detection Drug usage Ecology Ecosystem Environment Expeditions Future Gene Cluster Gene Expression Profile Genetic Genetic Transcription Genome Genome Scan Genomics Genotype Geology 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 Natural Products Neurodegenerative Disorders Operon Organism Pathogenicity Patients Pharmaceutical Preparations Pharmacopoeias Process Regulation Research Research Personnel Resistance Resolution Resources Role Sampling Source Statistical Data Interpretation Stimulus Surface Surveys Taxonomy Techniques Technology Testing Time Translations Tube Work analytical method anti-cancer base cohort comparative data mining drug candidate drug development drug discovery exhaust follow-up genome sequencing global health human disease human genomics insight instrument interest ion mobility metabolome metabolomics microbial microbiome microorganism novel therapeutics public health relevance pyrosequencing tool transcriptome virtual

项目摘要

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大部分药物的来源，因为次生代谢物、其衍生物或受其启发的化合物在临床中如此广泛，因此仍然存在很大的热情。然而，对次生代谢物发现工作的热情已经减弱，因为经过数十年对我们环境中候选药物的挖掘，容易进入的生态系统已经耗尽，而目前采用的发现方法是极其劳动密集型的，效率低。然而，最近廉价的基因组测序技术的出现明确地表明，迄今为止的努力通常只触及了现有天然化学多样性的表面。基因组学告诉我们，这些相同的生物体含有更多的基因蓝图——十到二十倍，但迄今为止，几乎没有任何简便的通用方法可以将这些蓝图转化为管中的分子。在此，我们解决了两个主要目标：为天然产物的发现开辟新的生态系统，并消除表达瓶颈以加速来自不寻常来源的微生物的天然产物的发现。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方法。捕获与新化合物发现和化学生态学相关的综合微生物代谢组信息。我们支持这些目标的三个目标包括三个主要具体目标：(1) 地下次生代谢的化学生物地质调查。（洞穴）生态系统，（2）开发生物合成过程的天然代谢激活以供发现，（3）为基因型提供刺激图谱，以合理选择化学和生物条件，诱导具有高表观生物合成能力的生物体的二次代谢。完成拟议的研究与人类健康高度相关，因为它将提供加速鉴定已经并将继续对人类健康产生重大影响的天然产物的方法。此外，发现新发现和重新发现的化合物其作用方式尚未确定，可能会提供新的治疗方法。