New Methodologies for Accelerating Natural Product Discovery

 描述（由申请人提供）：次级代谢产物是用于成功治疗生命垂危疾病的大部分药物的来源。由于次级代谢产物、其衍生物或受其启发的化合物在临床上如此广泛，因此对它们的持续发现仍然有很大的热情。然而，对次级代谢物发现工作的热情已经减弱，因为经过几十年的开采我们的环境中的候选药物，容易接近的生态系统已经耗尽，目前采用的发现方法是极其劳动密集型的，每个生物体的化合物产量低，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表明，迄今为止的努力只是触及了现有天然化学多样性的表面。虽然大多数生物体通常只产生一两种天然产物，但基因组学告诉我们，这些生物体包含的遗传蓝图要多得多--多十倍或二十倍。但是到目前为止，很少有人提供任何简单的可推广的方法来将这些蓝图翻译成试管中的分子。在此，我们解决了两个主要目标，即为天然产物发现打开新的生态系统，并消除表达瓶颈，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学相关的综合微生物代谢组中的信息。支持这些目标的三个目标包括三个主要的具体目标，即（1）地下（洞穴）生态系统次生代谢的化学代谢生态学调查，（2）开发生物合成过程的天然代谢活化，（三）为合理选择化学和生物条件提供基因型刺激图谱，这些条件诱导具有高表观生物合成的生物体的次级代谢。才能拟议研究的成功完成与人类健康高度相关，因为它将提供方法来加速识别已经并继续对人类健康产生重大影响的天然产品。此外，发现新发现和再发现的化合物的作用方式（其作用方式尚未确定）可以提供新的治疗剂。

 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.