Bioengineering natural product biosynthetic pathways for therapeutic applications

With the advent of next-generation DNA sequencing technologies, the number of microbial genome sequences has increased dramatically, revealing a vast array of new biosynthetic gene clusters. Genomics data provide a tremendous opportunity to discover new natural products, and also to guide the bioengineering of new and existing natural product scaffolds for therapeutic applications. Notably, it is apparent that the vast majority of biosynthetic gene clusters are either silent or produce very low quantities of the corresponding natural products. It is imperative therefore to devise methods for activating unproductive biosynthetic pathways to provide the quantities of natural products needed for further development. Moreover, on the basis of our expanding mechanistic and structural knowledge of biosynthetic assembly-line enzymes, new strategies for re-programming biosynthetic pathways have emerged, resulting in focused libraries of modified products with potentially improved biological properties. In this review we will focus on the latest bioengineering approaches that have been utilised to optimise yields and increase the structural diversity of natural product scaffolds for future clinical applications.

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► Highlights of recent methods for enhancing natural product yields, activating cryptic clusters, and biosynthetic engineering of natural products.
► Advances in genomics have allowed identification of numerous cryptic biosynthetic clusters.
► Exploitation of regulatory pathways has led to cryptic cluster activation and increased natural product titres.
► Combinatorial biosynthesis, mutasynthesis and protein engineering have led to new derivatives of natural products with modulated biological activity.