Warwick team cracks bacteria's cancer-drug assembly code
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- University of Warwick researchers published in Nature Communications the molecular basis for combinatorial biosynthesis of depsipeptide HDAC inhibitors, solving a decades-old puzzle about how bacteria naturally produce multiple variants of powerful anti-cancer drugs.
- Dr. Munro Passmore and colleagues identified small 'docking domains' — conserved molecular connectors that let a core PKS-NRPS hybrid production line recognize and pass its product to multiple enzyme partners, enabling nature's 'mix and match' drug assembly.
- The mechanism applies directly to Romidepsin (Istodax), an FDA-approved HDAC inhibitor for T-cell lymphomas, and to FR-901375, a chemically related compound whose bacterial production pathway had eluded scientists since its discovery.
- The team located the FR-901375 biosynthetic gene cluster in Pseudomonas chlororaphis subsp. piscium, confirming the finding through mass spectrometry of extracted metabolites.
- They validated the docking-domain model using AlphaFold structural prediction, carbene footprinting mass spectrometry, site-directed mutagenesis, and in vitro reconstitution of purified protein domains, plus gene-deletion studies confirming docking domains are essential in vivo.
- Prof. Greg Challis (Monash Warwick Alliance) called the result 'a blueprint to do what nature does, but better and faster,' with the team's stated next step being an expanded library of optimized candidates for cancers lacking adequate treatments.
Why it matters: The discovery removes the central bottleneck that has kept combinatorial biosynthesis of depsipeptide HDAC inhibitors stuck for years: chemists can now engineer new drug variants with superior potency, selectivity, and fewer side effects, directly serving patients with cancers — including T-cell lymphomas — where current treatment options remain limited.
