Exploring and expanding natural product chemical diversity

微生物次生代谢物是一种遗传编码的生物活性分子，由专门的代谢途径组装而成，这些代谢途径受到高度调节，并根据环境因素进行调节。作为进化的产物，它们是独特的启动子分子，为生产生物体执行关键任务。此外，它们是丰富的分子来源，可能有助于生产生物体控制入侵物种，并在获取营养方面获得优势。鉴于其内在的生物活性和生理作用，微生物天然产物几千年来一直是药物和害虫防治剂的丰富来源，最近又成为药物和重要的农业制剂，这并不奇怪。在过去的资助期内，我们的nserc资助的研究使我们能够探索微生物产生的天然产物的生产，生物化学，生态学和工程。我们已经收集了大约10000种来自环境的微生物。这个收藏在学术环境中是独一无二的，是通过各种屏幕探索和利用天然产物的资源。这些微生物中的大多数可以产生数十种天然产物，我们已经开发了一个结合全基因组测序和分析化学的平台，可以快速识别和纯化微生物提取物中的活性化合物。因此，我们很好地定位于探索微生物天然产物的生物学和化学。***目的：我们将通过一系列生物活性筛选扩大我们收集的遗传多样性并探索其化学多样性。我们的重点将放在改变微生物表型的分子上，如细胞形状、生理等。这些化合物可以作为微生物生态学的优良探针，并作为研究关键细胞生物学和生物化学的门户。此外，这类分子在农业和医药领域具有潜在的应用前景。***科学方法：我们将扩大我们的天然产品生产微生物的收集，强调稀有的属和来源。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，如细菌的圆形或丝状，病原菌对菌丝的形成或抑制，色素的产生等。启动子化合物将通过活性引导方法纯化，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。***意义：本研究项目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，并得到了NSERC过去的资助。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，在农业和医疗制剂的开发中具有潜在的应用前景

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.**