Integrated Omics Technologies for Natural Products Discovery

点击翻译按钮获取中文摘要

Many interactions in the natural world are governed by chemistry. For example, bacteria use small molecules to communicate, sequester nutrients, take over territory, and defend themselves from attack. Understanding the distribution and roles of these 'natural products' is essential to our understanding of global microbial ecology. This in turn has implications for many areas of society including agriculture, ecology, human health and biosecurity. Despite the importance of chemistry in these areas, we are still poorly equipped to answer many basic questions about microbial natural products. For example, it remains very difficult to identify all of the molecules produced by a single organism under a single culture condition. This challenge is amplified if we wish to identify all of the molecules made by libraries of microorganisms, and to determine which organisms have the capability of making which products. This proposal aims to create new tools to answer three basic questions in natural products science: 'how many compounds are in this mixture?', 'what are the structures of these compounds?', and 'how are these compounds made in Nature?'. To answer the first question ('how many compounds are in this mixture?') we will integrate a recently developed nuclear magnetic resonance (NMR) analysis platform from my laboratory with chemical profiling data from mass spectrometry (MS). This new hybrid tool will combine information from two of the most powerful profiling methods in organic chemistry (NMR and MS) to create a single platform capable of describing the chemical landscape of complex mixtures of products. To answer the second question ('what are the structures of these compounds?') we will use the information in our recently created database of microbial chemistry, the Natural Products Atlas, to create new algorithms for the direct prediction of compound class identity from mass spectrometry data. By developing a global understanding of the distribution of chemical classes in the natural world we can predict structural diversity within large bacterial libraries. To answer the final question ('how are these compounds made in Nature?') we will use a combination of genome sequencing and parallel stable isotope labeling to match natural products to the genes responsible for their production (biosynthetic gene clusters). By performing this analysis on a large library of 100 sequenced bacterial strains, we can begin to evaluate the chemical capacity of the natural world, and to understand the scope and limitations of chemical diversity in Nature. The central outcome of this work will be a suite of new tools designed to enable a more detailed understanding of the chemistry of the natural world. This has potential future benefit to Canada in the discovery of new treatments for crop diseases, development of a clearer understanding of how our own microbiomes influence human health, end even perhaps the discovery of the next generation of therapeutics.