Method Developed for the Biosynthesis of Meroterpenoids

A Kobe University team has developed a new method that enables bioengineered Escherichia coli bacteria to produce orsellinic acid-derived meroterpenoids, compounds with anticancer, anti-HIV, antidiabetic, and anti-inflammatory activities. Their rational design strategy created a platform for industrial production of these drug candidates.

OSA-derived meroterpenoids are naturally produced by Rhododendron species and have attracted considerable interest because of their broad-spectrum pharmacological properties. Their natural sources, however, have proven unreliable and expensive, limiting research progress. Previous microbial production of the core compound, orsellinic acid, achieved only low yields. According to ltsuki Tomita, first author of the paper published in Metabolic Engineering, “There are many examples where compounds appear promising in the literature but fail to advance sufficiently in evaluation or applied research due to supply issues. I began to feel this is less an issue with individual compounds and more a structural challenge facing natural products research as a whole.”

Tomita worked with a team of experts in rationally designing microorganisms for the production of a broad range of compounds. Using a combination of introducing appropriate genes from plants, fungi and bacteria, analyzing the organism’s metabolism and optimizing the culture conditions, the team created an industrial-scale production platform for these compounds.

They were able to produce 202 mg orsellinic acid per liter, a 40-fold improvement over prior microbial efforts and the first success in E. coli. “It is a significant achievement that we recreated a complex eukaryotic biosynthetic pathway in the bacterium E. coli, something that was previously thought difficult,”  Tomita explained.

The team also added a Rhododendron gene to complete biosynthesis of grifolic acid, selected for its anticancer and analgesic properties. While yields remain low, the engineered bacteria produced it successfully, and the group identified bottlenecks for future optimization.

Senior author Tomohisa Hasunuma said there is even wider potential: “In the short term, the platform established in this study can be immediately applied to the production and evaluation of related compounds and their derivatives. However, the rational design strategy employed here serves as a foundational technology for the production of various complex compounds using E. coli.”