In vivo production of psilocybin in E. coli
https://www.sciencedirect.com/science/article/pii/S109671761930309X

Highlights
• First example of psilocybin production in prokaryotic host.

• Genetic optimization shows high sensitivity to changes in transcriptional landscape.

• Pathway bottlenecks removed through fine-tuned optimization.

• Gram-scale production of psilocybin in Escherichia coli.


Abstract
Psilocybin, the prodrug of the psychoactive molecule psilocin, has demonstrated promising results in clinical trials for the treatment of addiction, depression, and post-traumatic stress disorder. The development of a psilocybin production platform in a highly engineerable microbe could lead to rapid advances towards the bioproduction of psilocybin for use in ongoing clinical trials. Here, we present the development of a modular biosynthetic production platform in the model microbe, Escherichia coli. Efforts to optimize and improve pathway performance using multiple genetic optimization techniques were evaluated, resulting in a 32-fold improvement in psilocybin titer. Further enhancements to this genetically superior strain were achieved through fermentation optimization, ultimIn vivo production of psilocybin in E. coliately resulting in a fed-batch fermentation study, with a production titer of 1.16 g/L of psilocybin. This is the highest psilocybin titer achieved to date from a recombinant organism and a significant step towards demonstrating the feasibility of industrial production of biologically-derived psilocybin.