Kobe University researchers have successfully engineered Escherichia coli bacteria to produce orsellinic acid, a core compound used in pharmaceuticals with anticancer, anti-HIV, antidiabetic, and anti-inflammatory properties. The breakthrough, published in the journal Metabolic Engineering, represents a 40-fold increase in production compared to previous microbial attempts and marks the first successful synthesis of the compound within E. Coli.
Plants, particularly species of Rhododendron, naturally produce orsellinic acid-derived meroterpenoids. However, sourcing these compounds directly from plants is often unreliable and expensive, hindering pharmacological research and potential drug development. Previous efforts to produce orsellinic acid through microbial fermentation yielded insufficient quantities for practical application.
The Kobe University team, led by bioengineer HASUNUMA Tomohisa and doctoral student TOMITA Itsuki, employed a “rational design strategy” to overcome these limitations. This involved introducing specific genes from plants, fungi, and bacteria into E. Coli, combined with detailed analysis of the bacteria’s metabolism and optimization of growth conditions. “It is a significant achievement that we recreated a complex eukaryotic biosynthetic pathway in the bacterium E. Coli, something that was previously thought difficult,” said Tomita.
The researchers achieved a production level of 202 milligrams of orsellinic acid per liter of bacterial culture. This success paves the way for industrial-scale production of the compound, addressing a critical bottleneck in natural product research. According to Tomita, supply issues often prevent promising compounds from advancing through evaluation and applied research. “I began to perceive this is less an issue with individual compounds and more a structural challenge facing natural products research as a whole,” he stated.
Building on their success with orsellinic acid, the team further engineered the bacteria to produce grifolic acid, a pharmacologically relevant compound known for its anticancer and analgesic properties. While successful, the production yield of grifolic acid remains a focus for further optimization, with the researchers already identifying potential areas for improvement.
Hasunuma emphasized the broader implications of this research. “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.”
The research was supported by funding from the Japan Society for the Promotion of Science (Program for Forming Japan’s Peak Research Universities (J-PEAKS)) and the Japan Science and Technology Agency. Collaboration with researchers from the University of Minho and the RIKEN Center for Sustainable Resource Science also contributed to the project.
