Study Explains How Bacteria Generate Multiple Cancer Compounds

A team from University of Warwick and Monash University has worked out how bacteria naturally produce multiple versions of powerful cancer therapies, a question that has puzzled drug developers for decades. The finding could speed up development of treatments for hard-to-treat cancers.

Combinatorial biosynthesis—harnessing bacterial enzymes to create drug variants—has long been a goal for scientists, but progress had stalled without an understanding of how the enzymes involved interact. 

Published in Nature Communications, the team’s work reveals how bacterial enzymes communicate and cooperate 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 it in the lab, the researchers have established an approach for 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 Munro Passmore. “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 analysis shows that small molecular regions, called docking domains, act as connectors between the core drug assembly machinery and the enzymes that build variable components. These docking domains use a conserved connection point that works with multiple different enzyme partners, which explains how bacteria generate structural diversity while keeping their drugs precise and effective.

The work also traces how these drug-producing systems evolved naturally, finding that the newly discovered compound likely arose from a related drug-producing system through gene duplications and recombinations.

Senior author Greg Challis added “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.”