Mutasynthesis of Physostigmines in Myxococcus xanthus

The alkaloid physostigmine is an approved anticholinergic drug and an important lead structure for the development of novel therapeutics. Using a complementary approach that merged chemical synthesis with pathway refactoring, we produced a series of physostigmine analogues with altered specificity and toxicity profiles in the heterologous host Myxococcus xanthus. The compounds that were generated by applying a simple feeding strategy include the promising drug candidate phenserine, which was previously accessible only by total synthesis.

Automated summary

By combining chemical synthesis with pathway refactoring, a series of physostigmine analogues with altered specificity and toxicity profiles were produced in the heterologous host. Among the compounds generated, the promising drug candidate phenserine was included, which was previously only accessible through total synthesis. This study provides a new approach for the development of novel therapeutics.