Rapid Engineering of Secondary Metabolite Gene Clusters in the Genomic Era

Next-generation sequencing has dramatically accelerated the identification of novel natural product pathways.  Warp Drive Bio is harnessing the emerging field of synthetic biology as it can be applied to natural product cluster and microbial strain engineering in order to address the growing demands of natural product production. The use of synthetic biology can be a powerful way to shortcut the process of engineered overexpression in native strains or by heterologous expression in optimized hosts. Once clusters are refactored and expression is detected, the combination of molecular biology and strain engineering can simplify the product mixture. A simpler product distribution often results in increased titer as the metabolic flux from the cluster funnels into a single species, which further facilitates compound purification. As compounds proceed into pre-clinical development it often becomes important to chemically modify the natural product scaffolds to enhance target engagement, PK/PD, etc., and some natural product scaffolds are not always amenable to modification by semisynthetic methods.  Warp has enabled a robust engineering platform to modify the biosynthetic machinery in a directed and site-specific manner. These modifications enable the creation of new chemical matter that preserves the special drug-like properties of these molecules while maintaining authentic production levels. Therefore, engineering of biosynthetic clusters at all stages of the drug discovery pipeline greatly enhances the success rate of developing natural products into useful therapeutics.