Abstract

Natural products represent a molecularly diverse, genetically-encoded ‘chemistry set’ which has been honed by evolution, and compounds based on natural products remain among the most valuable medicines ever introduced to the clinic. They include antibacterials, antivirals, antifungals, immunosuppressants, cholesterol-lowering agents, insecticides and an impressive array of anticancer compounds. On the other hand, the complexity of their structures hinders both chemical manipulation and total synthesis. The perceived difficulty of optimising an initial ‘hit’ into a patentable drug has led to a widespread disenchantment with natural products in drug discovery. Synthetic biology offers a new way to reconcile the obvious merits of natural product-based drugs with the demands of the drug development process. It has recently become possible to redesign the genes that encode the synthesis of such chemicals, to make precise changes in the structure. A collection of bacteria housing such altered genes can be used to produce ‘libraries’ of highly bioactive, patentable chemical entities, cheaply accessible by fermentation, and capable of further diversification by conventional medicinal chemistry. Such compounds can also be used as chemical genetic probes, to study fundamental biochemical mechanisms both in health and disease.