Researchers Decode Bacterial Enzyme System Creating Multiple Cancer Drugs

Researchers from the University of Warwick and Monash University have identified the mechanism by which bacteria generate multiple versions of potent anti-cancer drugs, solving a decades-old scientific puzzle. This breakthrough could enable the design of new cancer treatments by demonstrating how nature produces a variety of drug molecules using the same enzymatic machinery.

The study, published in Nature Communications, explains how bacterial enzymes communicate and cooperate to assemble a family of related anti-cancer compounds. Among these is Romidepsin (Istodax), an FDA-approved drug for certain blood cancers. By replicating this natural "mix and match" system in laboratory settings, the researchers have created a new approach for developing future cancer therapies.

Dr. Munro Passmore, Research Fellow at the University of Warwick's Department of Chemistry and the study’s first author, stated, “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.”

Bacterial Enzymes Use Molecular Connectors

The team discovered that small protein segments called ‘docking domains’ act as molecular connectors between the main drug-producing enzymes and those that add various chemical components. These docking domains share a common interaction site, enabling them to connect with multiple enzyme partners. This flexibility allows bacteria to produce a range of closely related drug molecules while ensuring the compounds remain effective.

The research also provides insight into the evolutionary development of these drug-producing systems. The newly identified compound likely originated from a related biosynthetic pathway through gene duplications and recombination events.

Professor Greg Challis, Monash Warwick Alliance Professor of Sustainable Chemistry, commented, “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.”

Implications for Cancer Drug Development

The focus of the study is on HDAC inhibitors, a class of medicines that block histone deacetylases—enzymes that regulate gene expression within cells. Romidepsin (Istodax) is a well-known drug in this category, approved for treating T-cell lymphomas.

Another compound, FR-901375, has long puzzled scientists because its bacterial biosynthetic pathway was unknown. This research identifies the missing pathway, revealing how bacteria produce this compound.

Like other HDAC inhibitors in this group, FR-901375 is a depsipeptide, a complex ring-shaped molecule. Bacteria synthesize these compounds using large protein complexes called PKS-NRPS hybrids, which combine polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) activities to assemble the drug from smaller building blocks.

The newly discovered docking domains function as connectors along this biological assembly line, enabling the transfer of partially assembled products between enzyme modules. This explains how bacteria naturally create multiple related drugs through combinatorial biosynthesis.

Methodology Behind the Discovery

The research team employed a combination of structural biology, biochemistry, genetics, and computational approaches to uncover this mechanism. Their work included bioinformatic searches to identify the FR-901375 biosynthetic gene cluster in Pseudomonas chlororaphis subsp. piscium, confirmed by mass spectrometry analysis of metabolites.

Laboratory experiments with purified protein domains demonstrated productive enzyme interactions, verified by intact protein mass spectrometry. AlphaFold computational modeling predicted protein complex structures, which were experimentally confirmed using carbene footprinting mass spectrometry to map protein interaction sites.

Site-directed mutagenesis tested the importance of key binding residues predicted by the models, while gene deletion experiments in bacterial strains showed that the docking domains are essential for drug production within living cells. Comparative analyses of biosynthetic gene clusters across multiple HDAC inhibitor-producing bacteria revealed conserved evolutionary features.

The researchers conclude that their findings offer a powerful framework for engineering new generations of anti-cancer drugs by adapting and enhancing nature’s own methods for constructing complex medicines.

Reference: “Molecular basis for depsipeptide HDAC inhibitor combinatorial biosynthesis” by Munro Passmore et al., 1 July 2026, Nature Communications. DOI: 10.1038/s41467-026-74383-4