A team of researchers at the University of Warwick and Monash University has solved a puzzle that's stumped drug developers for decades: how bacteria naturally create multiple versions of powerful cancer therapies. The breakthrough could accelerate development of new treatments for hard-to-treat cancers.
Harnessing bacterial enzymes to create drug variants, a strategy known as combinatorial biosynthesis, has long been a goal for scientists. But without understanding how these enzymes interact, progress has stalled.
Published in Nature Communications, a team of researchers have finally revealed how bacterial enzymes communicate and work together to assemble a family of related anti-cancer compounds. This family includes Romidepsin (Istodax), a clinically approved blood cancer treatment. By understanding this "mix and match" process, and replicating the principle in the lab, the researchers have established an approach to designing new therapies.
"For decades, we've known that bacteria can naturally produce multiple versions of powerful anti-cancer drugs, yet we had no idea how they achieved this," said first author Dr. Munro Passmore, Research Fellow, Department of Chemistry, University of Warwick. "This work finally cracks that code. We've identified how the different enzymes communicate and cooperate to produce these drug variants, something that has eluded researchers because the system is so elegantly economical. It's the breakthrough we needed to actually engineer these drugs ourselves."
The team's analysis reveals that small molecular regions, termed 'docking domains,' act as connectors between the core drug assembly machinery and the variable component-building enzymes. Crucially, these docking domains use a conserved connection point that is compatible with multiple different enzyme partners, a feature that explains how bacteria generate structural diversity while keeping their drugs precise and effective.
The work also traces how these drug-producing systems evolve naturally. The researchers found that the newly discovered compound likely evolved from a related drug-producing system through gene duplications and recombinations.
Prof. Greg Challis, Monash Warwick Alliance Professor of Sustainable Chemistry, University of Warwick and Monash University concludes: "This research gives us a blueprint to do what nature does, but better and faster. By reverse-engineering nature's evolutionary logic, we can now design synthetic pathways that generate new anti-cancer drug candidates with properties optimized for clinical use, such as superior potency, improved selectivity, fewer side effects. Our immediate goal is to build an expanded library of candidates for various cancers where new treatments are urgently needed. This discovery is moving us from understanding how the systems work to building new ones."
