Bioengineered E. coli could allow for industrial-scale plant-derived drugs

Kobe University researchers have engineered Escherichia coli to synthesise orsellinic acid-derived meroterpenoids with anticancer, anti-HIV, antidiabetic and anti-inflammatory potential, establishing a scalable microbial platform to address long-standing supply constraints in natural products research

Researchers at Kobe University have engineered the bacterium Escherichia coli (E. coli) to produce a class of plant-derived compounds with anticancer, anti-HIV, antidiabetic and anti-inflammatory activities, in a development that could transform the industrial supply of promising drug candidates.

The team focused on orsellinic acid-derived meroterpenoids, a group of natural products originally identified in a species of Rhododendron. These compounds have attracted attention because of their broad pharmacological potential. However, their extraction from plants has proved unreliable and costly. Variable growth conditions, low natural abundance and complex purification procedures have restricted access to sufficient quantities for preclinical evaluation and drug development.

Previous attempts to engineer microorganisms to produce orsellinic acid, the core structural scaffold for this class of compounds, had yielded only modest results. Limited titres and unstable production systems meant that microbial synthesis had not yet offered a viable alternative to plant extraction.

Itsuki Tomita, a doctoral student at Kobe University, Kobe, Japan, said that the challenge reflected a wider structural problem within natural products research.

“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,” Tomita said.

“I began to feel this is less an issue with individual compounds and more a structural challenge facing natural products research as a whole,” he added.

Tomita conducted the work in the laboratory of Dr. Tomohisa Hasunuma, a bioengineer who specialises in the rational design of microbial cell factories. The group has extensive experience in metabolic engineering, a discipline that aims to redesign cellular pathways to direct biochemical flux towards target molecules. Rather than rely on trial and error, rational design uses genetic information and metabolic modelling to introduce specific biosynthetic genes, predict pathway interactions and optimise culture conditions.

To construct the production platform, the researchers introduced selected genes from plants, fungi and bacteria into E. coli. They then analysed the host bacterium’s metabolic network to identify competing pathways and potential bottlenecks. Through iterative optimisation of gene expression levels and cultivation parameters, they established a strain capable of efficient orsellinic acid synthesis.

The team reported a production level of 202 milligrams of orsellinic acid per litre of culture medium. This figure represents a 40-fold increase compared with previous reports of microbial production. It also marks the first demonstration of orsellinic acid synthesis in E. coli; a host organism widely used in industrial biotechnology because of its well-characterised genetics and scalability.

Tomita said that the achievement demonstrated the feasibility of reconstructing complex eukaryotic biosynthetic pathways in a prokaryotic host. “It is a significant achievement that we recreated a complex eukaryotic biosynthetic pathway in the bacterium E. coli, something that was previously thought difficult,” he said.

Beyond production of the core scaffold, the researchers extended the pathway to synthesise a downstream pharmacologically active compound. They introduced an additional gene from Rhododendron to complete the biosynthesis of grifolic acid, a representative member of the meroterpenoid class known for potent anticancer and analgesic properties. Although the engineered strain successfully produced grifolic acid, the yield remained relatively low. The team has identified several metabolic bottlenecks that limit flux through the extended pathway and has outlined strategies for further optimisation.

Natural products have historically provided a substantial proportion of approved medicines, yet their development often stalls because of insufficient supply. Plant cultivation requires time, land and specific environmental conditions. Chemical synthesis can prove complex and economically unviable for structurally intricate molecules. Microbial production platforms therefore offer an attractive alternative, provided that sufficient yields can be achieved.

Hasunuma said that the short-term application of the platform lies in the rapid production and evaluation of related meroterpenoid derivatives.

“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,” he said.

“However, the rational design strategy employed here serves as a foundational technology for the production of various complex compounds using E. coli.”

By demonstrating that a complex plant pathway can be reconstructed and optimised in a bacterial host, the Kobe University team has provided a blueprint for the industrial biosynthesis of other structurally elaborate natural products.

For further reading please visit: 10.1016/j.ymben.2025.12.008