Researchers at the University of Warwick report they have identified how bacteria can reliably produce multiple versions of certain histone deacetylase (HDAC) inhibitor compounds, a finding they say could help scientists engineer new drug candidates inspired by these natural products.
A team at the University of Warwick has described how bacteria can generate multiple variants of a family of cyclic “depsipeptide” HDAC inhibitors—a group that includes romidepsin (Istodax), an FDA-approved drug used to treat T‑cell lymphomas.
In the study, the researchers report that small molecular regions they call “docking domains” act as connectors between different enzyme systems involved in assembling these compounds. The team says this connector system helps explain how bacteria can create a range of related molecules while maintaining the precision needed for the assembly line to function.
First author Dr. Munro Passmore said the work “finally cracks that code,” referring to longstanding uncertainty about how the enzyme components coordinate. Co-author Prof. Greg Challis said the findings provide a “blueprint” for designing synthetic pathways that could generate new candidates with properties more suitable for clinical use, including improved selectivity and fewer side effects.
According to the University of Warwick release, the work focuses on depsipeptide HDAC inhibitors and reports the identification of the biosynthetic gene cluster for FR‑901375 in Pseudomonas chlororaphis subsp. piscium. The researchers said they used a combination of computational and laboratory approaches—including bioinformatic database searches and gene deletion experiments—to validate key elements of the pathway.
The research was published in Nature Communications under the title “Molecular basis for depsipeptide HDAC inhibitor combinatorial biosynthesis.”
