Exploring and expanding natural product chemical diversity

微生物次级代谢物是由基因编码的生物活性分子，通过特定的代谢途径组装，这些代谢途径受到高度调节并根据环境线索进行调整。作为进化的产物，它们是独特的激发子分子，为生产生物体执行关键任务。此外，它们是丰富的分子来源，可能有助于生产控制入侵物种的生物体，并在获取营养方面获得优势。鉴于其固有的生物活性和生理作用，微生物天然产物数千年来一直作为药物和害虫控制剂的丰富来源，最近又作为药物和农业上重要的试剂，这并不奇怪。在过去的资助期间，我们的NSERC资助的研究使我们能够探索微生物生产的天然产品的生产，生物化学，生态学和工程。 我们已经收集了约10，000种环境来源的微生物。该系列在学术环境中是独一无二的，并通过各种屏幕作为探索和利用天然产品的资源。这些生物中的大多数可以产生数十种天然产物，我们开发了一个平台，将全基因组测序和分析化学相结合，可以快速识别和纯化微生物提取物中的活性化合物。因此，我们有能力探索微生物天然产物的生物学和化学。 目的：我们将扩大我们的收藏品的遗传多样性，并通过一系列生物活性筛选来探索其化学多样性。我们的重点将是改变微生物表型的分子，例如细胞形状，生理学等。这些化合物可以作为微生物生态学的优秀探针，并作为研究关键细胞生物学和生物化学的门户。此外，这些分子是具有农业和医学应用的试剂的潜在先导物。 科学方法：我们将扩大我们的天然产品生产微生物的收集，强调稀有属和来源。特别是与药用植物相关的内生菌将被探索。这些将用于筛选新的微生物表型，如细胞形状的变化，例如细菌的变圆或变圆，病原真菌对菌丝的形成或抑制，色素的产生等。激发子化合物将通过活性导向方法纯化，确定相应生物合成基因簇的序列，并建立生物合成的生物化学。 重要性：该研究计划建立在我们实验室在天然产物生物学和化学方面20多年的努力基础上，由过去的NSERC赠款。这项工作为更好地理解天然产物生物学和化学生态学奠定了基础，并具有在农业和医疗制剂开发中应用的潜力。

Microbial secondary metabolites are genetically encoded bioactive molecules assembled by dedicated metabolic pathways that are highly regulated and tuned to environmental cues. As products of evolution, they are unique elicitor molecules that perform critical tasks for the producing organisms. Furthermore, they are rich sources of molecules that likely serve producing organisms in control of encroaching species and to gain advantage in accessing nutrients. Given their intrinsic bioactivity and physiological effects, it is not surprising that microbial natural products have served as a rich source of medicines and pest control agents for millennia and more recently as drugs and agriculturally important agents. Over the past grant period, our NSERC-funded research has enabled us to explore the production, biochemistry, ecology and engineering of microbially produced natural products. We have amassed a collection of ~10,000 environmentally sourced microbes. This collection is unique in an academic environment and is serving as a resource to explore and exploit the natural products through a variety of screens. Most of these organisms can produce dozens of natural products and we have developed a platform that combines whole genome sequencing and analytical chemistry to rapidly identify and purify active compounds from microbial extracts. We are therefore well positioned to explore the biology and chemistry of microbial natural products. Objectives: We will expand the genetic diversity of our collection and explore its chemical diversity through a series of screens for biological activities. Our focus will be on molecules that alter microbial phenotype e.g. cell shape, physiology, etc. These compounds can serve as excellent probes of microbial ecology and serve as gateways to study critical cellular biology and biochemistry. Furthermore, such molecules are potential leads for agents with application in agriculture and medicine. Scientific approach: We will expand our collection of natural product-producing microbes emphasizing rare genera and sources. In particular endophytes associated with medicinal plants will be explored. These will be used in screens for novel microbial phenotype such as changes in cell shape e.g. rounding or filamentation of bacteria, formation or inhibition of hyphae by pathogenic fungi, production of pigments, etc. Elicitor compounds will be purified by activity-guided methods, the sequence of the corresponding biosynthetic gene clusters determined, and the biochemistry of biosynthesis established. Significance: This research program builds on over 20 years of effort in our lab in natural product biology and chemistry supported by past NSERC grants. This work lays the foundation for better understanding of natural product biology and chemical ecology with the potential for application in the development of agricultural and medical agents.