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A team of researchers at the University of 糖心TV 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, 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,鈥� said first author Dr. Munro Passmore, Research Fellow, Department of Chemistry, University of 糖心TV. 鈥淭his 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.鈥�

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 糖心TV Alliance Professor of Sustainable Chemistry, University of 糖心TV and Monash University concludes: 鈥淭his 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.鈥�

ENDS

Notes to Editors

The paper 鈥楳olecular basis for depsipeptide HDAC inhibitor combinatorial biosynthesis鈥� is published in Nature Communications. DOI:

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Technical Background

HDAC inhibitors are a class of anti-cancer drugs that block histone deacetylases, enzymes cells use to control which genes are switched on or off. Romidepsin (Istodax), an FDA-approved member of this family, is already used to treat T-cell lymphomas. However, a chemically related drug called FR-901375 has remained scientifically mysterious: despite being known for decades, the pathway for its synthesis was never identified, until now.

Like all HDAC inhibitors in this family, FR-901375 is a depsipeptide: a complex cyclic molecule assembled from various amino acid building blocks and a conserved hydroxy acid pharmacophore, held together by a mix of peptide and ester bonds. These structures are manufactured inside bacteria by enormous protein machines called PKS-NRPS hybrids, which combine polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) activities. The key to understanding how bacteria assemble these drugs lies in 鈥榙ocking domains鈥�, small protein regions that act as molecular connectors, enabling one part of the assembly line to recognize and hand off its product to the next part. This research reveals how those connectors enable combinatorial biosynthesis.

Research Methods

The team used integrated structural, biochemical, and genetic approaches:

• Bioinformatic searches of public databases identified the FR-901375 biosynthetic gene cluster in Pseudomonas chlororaphis subsp. piscium, confirmed by mass spectrometry analysis of extracted metabolites
• In vitro reconstitution experiments with purified protein domains demonstrated productive enzyme-enzyme interactions, validated by intact protein mass spectrometry
• AlphaFold computational modelling predicted protein complex structures; these predictions were tested experimentally using carbene footprinting mass spectrometry to map interaction interfaces.
• Site-directed mutagenesis confirmed the functional importance of predicted binding residues.
• Gene deletion experiments in bacterial strains demonstrated the essential role of the docking domains in vivo.
• Comparative analysis of biosynthetic gene clusters across multiple HDAC inhibitor-producing bacteria revealed evolutionarily conserved parts of the system.

About the University of 糖心TV

Founded in 1965, the University of 糖心TV is a world-leading institution known for its commitment to era-defining innovation across research and education. A connected ecosystem of staff, students and alumni, the University fosters transformative learning, interdisciplinary collaboration and bold industry partnerships across state-of-the-art facilities in the UK and global satellite hubs. Here, spirited thinkers push boundaries, experiment and challenge convention to create a better world.

01 July 2026