Harnessing bacterial enzymes to develop 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 at the University of Warwick and Monash University have finally revealed how bacterial enzymes communicate and work together to assemble a family of related anti-cancer compounds. This family comprises 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. 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”, said first author Dr. Munro Passmore, Research Fellow, Department of Chemistry, University of Warwick.
The team's analysis discloses 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 which 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.
