Colibactin: More Than a New Bacterial Toxin Original paper

What was reviewed?

This paper reviewed the bacterial genotoxin colibactin and the pks genomic island that encodes its biosynthesis, with emphasis on where pks-positive bacteria appear in humans, how colibactin matures from a “prodrug” into an active genotoxin, and what host effects follow exposure. The authors framed colibactin as a microbiota-linked toxin that triggers DNA double-strand breaks, chromosomal instability, and cell-cycle arrest, then connects those cellular injuries to downstream clinical relevance such as carcinogenesis and invasive infections.

Who was reviewed?

Because this is a review, it integrated evidence across studied populations and models rather than enrolling a single cohort. It summarized human carriage studies showing pks+ E. coli in stools (about 12–32% prevalence) and in neonates (around 33% in one Swedish cohort and 26.9% in a French cohort), and it also drew on clinical isolate studies in urosepsis, prostatitis, neonatal meningitis, and blood cultures. The review further noted pks distribution in other Enterobacteriaceae such as Klebsiella pneumoniae and referenced animal and cell models that link pks-positive bacteria to epithelial DNA damage and tumor phenotypes.

What were the most important findings?

For a microbiome signatures database, the key “signature” is functional: colonization or infection with pks-positive Enterobacteriaceae, especially B2 phylogroup E. coli that often co-carry other virulence traits. The review underscored that colibactin-producing bacteria drive DNA damage that can lead to epithelial senescence and immune-cell apoptosis, and it tied that harm to a defined maturation pathway in which ClbM transports precolibactin into the periplasm, ClbP cleaves the prodrug side chain to generate mature colibactin, and ClbS protects bacteria by inactivating the genotoxic activity via cyclopropane hydrolase function. Structurally, the authors highlighted motifs linked to genotoxicity—cyclopropane “warheads” and DNA-interacting thiazole/bithiazole features—and they pointed to evidence that pks+ E. coli can induce DNA interstrand cross-links that feed into double-strand breaks.

What are the greatest implications of this study/ review?

Clinically, this review supports treating pks positivity as a meaningful microbial risk marker because it links a specific bacterial gene island to a clear mechanism—DNA injury with senescence/apoptosis—and to disease settings that matter to clinicians, including colorectal cancer and severe invasive infections. It also highlights an actionable therapeutic concept: the authors describe that inhibitors targeting the colibactin pathway (“Clb” inhibitors) have already shown proof-of-concept potential to prevent deleterious effects, which makes toxin-pathway blockade an attractive alternative to broad microbiome disruption. At the same time, they caution clinicians to keep context in view, because the pks island can also drive anti-inflammatory, analgesic, and antibiotic activities, so precision strategies should aim to reduce genotoxic output without discarding beneficial functions.