The re-emergence of natural products for drug discovery in the genomics era

Key Points Natural products continue to be an important source of leads for new medicines, despite reduced interest from large pharmaceutical companies. Screening collections of natural products can be assembled economically to provide excellent coverage of drug-like chemical space and in formats that are compatible with high-throughput bioassays. Metabolomics enables the rapid identification of novel compounds in complex mixtures of natural products and also provides a means to monitor the production of target molecules during fermentation or other production processes. Metagenomics and other genetic engineering techniques are enabling the production of target compounds in convenient systems, breaking away from the bottleneck otherwise created by microorganisms that are difficult to culture. Examples of recent and current applications of natural products are described for the discovery of antimicrobials and for inhibitors of protein–protein interactions, particularly as anticancer agents. The screening of natural products for lead molecules is an attractive strategy, as most natural products fall within biologically relevant chemical space. In this Review, Harvey, Edrada-Ebel and Quinn discuss how advanced screening, metabolomics and metagenomics approaches can be used in the identification, validation and production of naturally sourced compounds, and highlight examples of naturally derived antimicrobials and inhibitors of protein–protein interactions. Natural products have been a rich source of compounds for drug discovery. However, their use has diminished in the past two decades, in part because of technical barriers to screening natural products in high-throughput assays against molecular targets. Here, we review strategies for natural product screening that harness the recent technical advances that have reduced these barriers. We also assess the use of genomic and metabolomic approaches to augment traditional methods of studying natural products, and highlight recent examples of natural products in antimicrobial drug discovery and as inhibitors of protein–protein interactions. The growing appreciation of functional assays and phenotypic screens may further contribute to a revival of interest in natural products for drug discovery.