Exploring and expanding natural product chemical diversity

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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.