Bacteria have been quietly making several versions of powerful cancer drugs for decades. Now scientists say they know how.
Researchers at the University of Warwick have identified how bacterial enzymes work together to build a family of closely related anti-cancer compounds, including Romidepsin, sold as Istodax, which is approved by the US Food and Drug Administration for some blood cancers.
The study, published in Nature Communications, describes how bacteria use small molecular regions called docking domains to connect the main drug-building machinery with enzymes that add different components.
Those docking domains share a conserved connection point, which lets them interact with multiple enzyme partners. The researchers said that flexible system helps bacteria make a range of related drug molecules while keeping the precision needed for the compounds to stay effective.
“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,” first author Dr Munro Passmore, a research fellow in the Department of Chemistry at the University of Warwick, said.
“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 researchers said the finding could make it easier to engineer new treatments based on natural drug systems, including improved versions of existing medicines.
The work focused on HDAC inhibitors, a class of anti-cancer medicines that block histone deacetylases, enzymes involved in regulating which genes are switched on or off inside cells.
Romidepsin is one example. Another related compound, FR-901375, had been known for decades, but scientists had not identified the biological pathway bacteria use to produce it until now.
FR-901375 belongs to a group of cyclic molecules called depsipeptides. These compounds are built from amino acid building blocks and a conserved hydroxy acid pharmacophore, linked by peptide and ester bonds.
Inside bacteria, they are assembled by large protein complexes known as PKS-NRPS hybrids, which combine the activities of polyketide synthase and nonribosomal peptide synthetase.
The study found that docking domains act as molecular connectors, letting one part of the production line recognise and pass its product to the next. The researchers said that mechanism allows combinatorial biosynthesis, the process that lets bacteria naturally generate multiple drug variants.
To work out how the system functions, the team used structural biology, biochemistry, genetics and computational modelling.
Their study included bioinformatic searches of public databases that identified the FR-901375 biosynthetic gene cluster in Pseudomonas chlororaphis subsp. piscium. The researchers confirmed those findings with mass spectrometry analysis of extracted metabolites.
They also carried out in vitro reconstitution experiments with purified protein domains, AlphaFold modelling of protein complex structures, carbene footprinting mass spectrometry, site-directed mutagenesis and gene deletion studies in bacterial strains.
The researchers said comparative analysis of biosynthetic gene clusters from several HDAC inhibitor-producing bacteria also showed conserved features shared across these natural drug-making systems.
The study also suggested the newly identified compound most likely arose from a related drug-producing pathway through gene duplication and recombination over time.
Professor Greg Challis, Monash Warwick Alliance professor of sustainable chemistry at the University of Warwick and Monash University, said the work offered a way to design new anti-cancer drug candidates.
“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.”
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