Scientists have lastly uncovered how micro organism naturally create a number of variations of highly effective anti-cancer medication, fixing a thriller that has pissed off researchers for many years.
Researchers from the University of Warwick and Monash University have solved a long-standing mystery about how bacteria naturally produce multiple versions of powerful cancer-fighting compounds. Their discovery could help scientists develop new treatments for cancers that are difficult to treat by revealing how nature creates a wide variety of drug molecules from the same biological machinery.
For years, researchers have wanted to harness bacterial enzymes to produce new drug variants through a process known as combinatorial biosynthesis. However, progress has been limited because scientists did not understand how the enzymes worked together to assemble different compounds.
Now, in a study published in Nature Communications, the research team has uncovered how bacterial enzymes communicate and cooperate to build an entire family of related anti-cancer molecules. One member of this family is Romidepsin (Istodax), an FDA-approved treatment for certain blood cancers. By decoding this natural “mix and match” system and recreating its principles in the laboratory, the researchers say they have established a new strategy for designing future cancer 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.”
Tiny Molecular Connectors Unlock Nature’s Drug Factory
The researchers discovered that small protein regions known as ‘docking domains’ serve as molecular connectors between the main drug-producing machinery and the enzymes responsible for adding different chemical components.
These docking domains share a common connection point that allows them to interact with several different enzyme partners. That flexibility enables bacteria to generate a variety of closely related drug molecules while maintaining the precision needed for the compounds to remain effective.
The study also sheds light on how these drug-producing systems evolved over time. According to the researchers, the newly identified compound most likely originated from a related drug-producing pathway through a series of gene duplications and genetic recombination events.
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.”
How the Discovery Could Improve Cancer Drug Development
The research focuses on a group of medicines called HDAC inhibitors, which work by blocking histone deacetylases, enzymes that regulate which genes inside a cell are switched on or off. Romidepsin (Istodax), one of the best-known drugs in this class, is already approved to treat T-cell lymphomas.
Another closely related compound, FR-901375, has puzzled scientists for decades because researchers could never determine exactly how bacteria produced it. This study finally identifies that missing biosynthetic pathway.
Like other HDAC inhibitors in this family, FR-901375 belongs to a class of complex ring-shaped molecules called depsipeptides. Bacteria manufacture these compounds using massive protein complexes known as PKS-NRPS hybrids, which combine polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) activities to assemble the drug from smaller molecular building blocks.
The newly identified docking domains act like connectors along this biological assembly line, allowing one section of the machinery to pass its partially built product to the next. This molecular handoff explains how bacteria naturally create multiple related drugs through combinatorial biosynthesis.
How Researchers Solved the Mystery
To uncover this mechanism, the team combined structural biology, biochemistry, genetics, and computational analysis.
Their research included:
- Bioinformatic searches of public databases to identify the FR-901375 biosynthetic gene cluster in Pseudomonas chlororaphis subsp. piscium, followed by mass spectrometry analysis to confirm the metabolites produced.
- Laboratory experiments using purified protein domains that demonstrated productive enzyme interactions, verified through intact protein mass spectrometry.
- AlphaFold computational modeling to predict protein complex structures, with those predictions confirmed experimentally using carbene footprinting mass spectrometry to map where the proteins interact.
- Site-directed mutagenesis to verify the importance of key binding residues predicted by the models.
Gene deletion experiments in bacterial strains showing that the docking domains are essential for the drug-producing process inside living cells. - Comparative studies of biosynthetic gene clusters from multiple HDAC inhibitor-producing bacteria, revealing conserved evolutionary features shared across these systems.
The researchers believe the findings provide a powerful framework for engineering new generations of anti-cancer drugs by borrowing and improving upon nature’s own methods for building complex medicines.
Reference: “Molecular basis for depsipeptide HDAC inhibitor combinatorial biosynthesis” by Munro Passmore, Xinyun Jian, Xinyi Zhao, Emmanuel L. C. de los Santos, Douglas M. Roberts, Józef R. Lewandowski, Matthew Jenner, Lona M. Alkhalaf and Gregory L. Challis, 1 July 2026, Nature Communications.
DOI: 10.1038/s41467-026-74383-4
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