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Merck

In vivo production of psilocybin in E. coli.

Metabolic engineering (2019-09-25)
Alexandra M Adams, Nicholas A Kaplan, Zhangyue Wei, John D Brinton, Chantal S Monnier, Alexis L Enacopol, Theresa A Ramelot, J Andrew Jones
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, ultimately 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.

MATERIALS
Product Number
Brand
Product Description

Supelco
Serotonin, analytical standard
Sigma-Aldrich
4-Hydroxyindole, 99%