Scientists have identified the molecular mechanism bacteria use to naturally produce multiple versions of a powerful class of cancer drugs, resolving a question that had puzzled researchers for decades.
The discovery, published in Nature Communications by researchers at the University of Warwick, could accelerate the development of new treatments for cancers that remain difficult to treat, according to the university.
For years, scientists have wanted to harness bacterial enzymes to generate new drug variants through a process called combinatorial biosynthesis. Progress had been limited, however, because researchers did not understand how the enzymes involved coordinate their work.
The new study shows how bacterial enzymes communicate with one another to build a family of closely related anti-cancer compounds. That family includes Romidepsin, sold as Istodax, an FDA-approved treatment for certain blood cancers.
"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 Dr. Munro Passmore, the study's first author and a Research Fellow in the Department of Chemistry at the University of Warwick. "This work finally cracks that code."
Tiny Connectors, Big Implications
At the heart of the discovery are small molecular regions called "docking domains," which act as connectors between the core drug-building machinery and the enzymes that add different chemical components. These docking domains share a conserved connection point that lets them interact with multiple enzyme partners, allowing bacteria to produce a variety of related drug molecules while keeping the precision needed for the compounds to work effectively.
The research also traces the evolutionary origin of one compound in this family, FR-901375, which has been known chemically for decades but whose biological production pathway had never been identified. According to the researchers, it likely evolved from a related drug-producing pathway through gene duplication and recombination.
The drugs in question belong to a class known as HDAC inhibitors, which block enzymes called histone deacetylases that help regulate which genes are switched on or off inside cells. Romidepsin, part of this class, is already used to treat T-cell lymphomas. The compounds are built inside bacteria by massive protein complexes combining polyketide synthase and nonribosomal peptide synthetase activity, known as PKS-NRPS hybrids.
To map out the process, the team combined structural biology, biochemistry, genetics and computational modeling, including AlphaFold-based structure predictions, mass spectrometry, gene deletion studies and site-directed mutagenesis, ultimately confirming that the docking domains are essential for the system to function.
Prof. Greg Challis, Monash Warwick Alliance Professor of Sustainable Chemistry at the University of Warwick and Monash University, said the findings offer more than an explanation of natural chemistry. "This research gives us a blueprint to do what nature does, but better and faster," he said, adding that the team's immediate goal is to build an expanded library of drug candidates for cancers where new treatments are urgently needed.