High-Throughput Discovery of Natural Products Using Hundreds of Bacterial Genomes and a Correlative MethodPublic Deposited
Natural products provide a renewable resource of novel chemical structures with relevance to the pharmaceutical, agricultural and materials industries. Genome sequencing has revealed that these industries currently rely on only a fraction of the number of natural products that exist in nature. Based on the impact that known natural products have already had, undiscovered natural products represent a massive opportunity. The challenge in discovering new natural products in the 21st century is that conventional methods of discovery, by their nature, can only scratch the surface of natural chemical diversity. New discovery methods are needed to achieve deterministic mining of the global catalogue of natural products at scale. A correlative mass spectrometry and genomics enabled approach was developed and used to construct a functional map of bacterial secondary metabolism. This correlative approach was applied toward the discovery of a new tetrapeptide natural product. While the correlative ‘omics approach is broadly applicable to cultivable natural product producing microbes, alternative methods still are needed to access the cryptic and uncultivable biosynthesis. Here, the use of a cell-free protein synthesis system based on bacterial lysate is explored as a platform for heterologous expression of secondary metabolite biosynthesis genes.
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