A class of cancer medicines that bacteria have been quietly assembling for millions of years is now a little less mysterious. Researchers at the University of Warwick and Monash University report in Nature Communications that they have worked out how microbes build multiple related versions of powerful anti-cancer compounds — and how that natural process might be reproduced, and improved, in the laboratory.
The compounds belong to a family of HDAC inhibitors, drugs that block histone deacetylases, the enzymes cells use to control which genes are switched on or off. One member, romidepsin (sold as Istodax), is already FDA-approved to treat T-cell lymphomas. A close chemical relative called FR-901375 has been known for decades, yet no one had established how bacteria actually make it. The new study finally identifies that pathway, tracing it to a biosynthetic gene cluster in the bacterium Pseudomonas chlororaphis subsp. piscium.
Molecular connectors that mix and match
At the centre of the finding are small protein regions the team calls "docking domains." Inside bacteria, these depsipeptide drugs are stitched together by enormous molecular machines known as PKS-NRPS hybrids — assembly lines that fuse a conserved, metal-binding core to a variable "cap" that differs from one family member to the next. The docking domains serve as the connectors between those two halves, letting one section of the line recognise its partner and pass along its half-finished product.
What makes the system so economical, the researchers found, is that these connectors share a conserved attachment point compatible with several different enzyme partners. That interchangeability is what allows bacteria to generate a range of related drugs while keeping each one precise enough to remain effective.
To establish this, first author Dr Munro Passmore and colleagues combined bioinformatic database searches, mass spectrometry, laboratory reconstitution of purified enzymes, AlphaFold structure predictions, carbene-footprinting experiments, targeted mutations and gene-deletion tests in living bacteria. Comparing gene clusters across several HDAC-inhibitor-producing microbes also indicated that the pathway evolved from an older one through gene duplication and recombination.
The practical hope is a quicker route to new treatments. "This research gives us a blueprint to do what nature does, but better and faster," said Prof. Greg Challis of the University of Warwick and Monash University. By reverse-engineering that evolutionary logic, the team aims to design synthetic pathways that yield new drug candidates with greater potency, improved selectivity and fewer side effects — starting with an expanded library aimed at cancers where new treatments are urgently needed.