Universal Characterization of Natural Product Libraries

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Organic molecules play a central role in many biological processes, from signaling molecules used by insects, to the development of the next generation of drugs for human diseases. These naturally occurring organic molecules are known as ‘natural products’. To study these compounds effectively, scientists must be able to separate individual molecules from the complex mixtures typically found in extracts from biological samples, and identify each of these individual constituents. The main objectives of this grant are to develop new analytical chemistry tools for this identification step, and to use these new tools to explore the distributions, origins and functions of naturally occurring compounds in bacteria. Currently there are approximately 30,000 known natural products in the bacterial world, making confident identification of these compounds a daunting analytical challenge. This grant aims to address this issue in four steps. Firstly we will create a universal database of all known bacterial natural products, and analyze the similarities and differences between their structures to produce a natural products ‘Atlas’ that describes the chemical landscape occupied by these naturally occurring compounds. Secondly, we will use nuclear magnetic resonance (NMR) spectroscopy to define all the diagnostic NMR signals for molecules present in our in-house natural products library. Thirdly, we will use these NMR data in conjunction with mass spectrometric (MS) data to determine the unique set of NMR and MS features that describe each compound in the library. Finally, we will develop new computational tools that use this set of NMR and MS features to connect chemical constituents to individual compounds in the natural products Atlas, therefore defining the complete composition of every extract in the natural products library. In addition to solving this outstanding analytical chemistry challenge, our laboratory is also interested in the biochemical origin of these natural products. To address this question we will use isotopically labeled precursors to track the incorporation of precursors into natural products during bacterial cell growth. Using a unique set of labeled precursors in conjunction with the analytical platform described above we will develop a method for the systematic determination of the biochemical origin of all natural products from a given bacteria strain, and create computational tools to link these molecules to their producing genes from whole genome sequences. Finally, we will use the analytical platform to explore the chemical diversity of a new and understudied class of bacteria, from the genus Burkholderia. The goal of this work is to examine the chemical diversity produced by these organisms, and to test the hypothesis that novel microbial diversity can help us discover unique natural products with future basic science and drug development applications.