Published in Science, the Harvard-led study details the structure of the DNA lesion caused by colibactin, marking a breakthrough in understanding toxin–DNA interactions.

Cross-linking occurs at a defined site due to the toxin’s unstable, positively charged core binding the negatively charged AT-rich minor groove, functioning like a lock‑and‑key.

Mutations attributed to colibactin are enriched in tumors from younger patients, suggesting early-life exposure to E. coli-rich microbiota may influence early-onset colorectal cancer risk.

Colibactin, a toxin produced by certain gut bacteria, damages DNA with a reactive core and “warhead” components, driving specific mutations linked to colon cancer.

Researchers connected colibactin’s structure to distinctive mutation fingerprints found in about 5% to 20% of colon cancers, suggesting diagnostic tests and improved risk assessment for exposure.

Researchers produced colibactin in living bacteria and used inline production to study its effects, employing gel sequencing, mass spectrometry, and NMR to map cross-linking and structure.

Mass spectrometry and NMR determined colibactin’s mechanism at the atomic level by growing toxin-producing bacteria adjacent to DNA to observe interactions.

The study used living gut microbes to produce colibactin and baited it with preferred DNA sequences to reveal its structure through MS and NMR.

Colibactin forms interstrand cross-links by acting as a DNA bridge, targeting AT-rich sequences in the minor groove to permanently link DNA strands.

The work points to potential health benefits: improved cancer risk screening, targeted treatments, and microbiome or dietary interventions to lower exposure to colibactin-producing bacteria.

These findings position colibactin-producing bacteria as a promising target for colorectal cancer prevention and pave the way for future research and interventions.

Colibactin preferentially cross-links AT-rich DNA due to a tighter, negatively charged minor groove, helping explain the mutation patterns seen in colorectal cancers.

This discovery explains the characteristic DNA mutations in colorectal cancer patients and lays the groundwork for diagnostics and therapeutics aimed at neutralizing colibactin or reducing its producing bacteria in the gut.

Harvard researchers emphasize cross‑department collaboration as essential to tackling colibactin, from producing enough material for structural work to integrating diverse expertise.

Initial challenges included isolating the unstable colibactin molecule; a microbial production approach enabled characterization of the true molecule and its DNA interaction.

The unstable, nitrogen-rich core of colibactin guides sequence recognition, while attached nitrogen- and carbon-containing arms facilitate DNA binding.

Experts view this as a major advance after nearly two decades of investigation, with implications for understanding colorectal cancer and developing preventive or therapeutic strategies.