P136: Enabling natural product drugs by biosynthetic engineering

Natural products (NPs) have historically played an important role in drug discovery. The combination of NPs or compounds derived from or inspired by them account for up to half of the drugs approved over the years. NPs occupy a distinct chemical space compared to available synthetic compounds used in screening collections, which should make the former a valuable addition to screening libraries. However, investment in NPs by pharmaceutical companies has decreased over the last decades. Challenges unique to NPs include sourcing (tractability and scalability), time and cost associated with isolation/identification and chemical structure complexity.

Recent developments in genomics, the genetics of NP biosynthesis, and biosynthetic engineering are playing an ever-increasing role in facilitating the NP drug discovery process. Examples include i) genome mining to discover new compounds; ii) activation of “silent” pathways by targeting regulatory genes or by engineering alternative promoters; iii) heterologous expression of biosynthetic gene clusters to overcome limitations with the native host (e.g. slow growth, genetic intractability); and iv) biosynthetic engineering directed at increasing yields and/or modifying the NP chemical structure.

 In this presentation, I will give examples from our laboratory on the application of biosynthetic engineering to overcome potential limitations associated with natural product drugs, such as supply.