An international team of researchers announced on Mar. 13 a significant breakthrough in the production of doxorubicin, a key chemotherapy drug. The study identifies and resolves molecular bottlenecks that have limited the natural production of this medication for more than five decades.
Doxorubicin has been used since the 1970s to treat various cancers, including breast cancer, bladder cancer, lymphomas, and carcinomas. More than one million patients receive this treatment each year. Despite its importance, bacteria naturally produce doxorubicin inefficiently, leading pharmaceutical companies to rely on costly and complex semi-synthetic manufacturing processes.
The research was conducted through collaboration among six laboratories: the University of Turku in Finland, three laboratories in the United States, and two in Leiden, the Netherlands. The teams identified three main constraints that hinder high-yield production of doxorubicin. They found that specific redox partners named Fdx4 and FdR3 are essential for providing electron flow to power the drug-producing enzyme. Additionally, they discovered that a protein called DnrV acts as a molecular sponge by binding doxorubicin so it does not inhibit its own synthesis machinery.
Using X-ray crystallography, researchers visualized the enzyme responsible for producing doxorubicin and observed that the drug molecule sits in an unfavorable position within the enzyme. This finding explains why natural production rates have been slow.
By addressing these issues, scientists engineered a new bacterial strain capable of producing 180% more doxorubicin than current industrial standards. To commercialize these advances, Meta-Cells Oy was established last year at the University of Turku with plans to develop sustainable manufacturing methods for antibiotics and anti-cancer agents.
This development could lead to cleaner and more reliable supplies of life-saving medicines as biosynthetic production methods replace traditional approaches.
