pks genomic island (Colibactin biosynthetic gene cluster) (pks island)

The pks genomic island is a 54-kilobase pathogenicity island found in certain strains of Escherichia coli, notably those of the B2 phylogroup, which encodes the biosynthetic machinery for colibactin [1]. Colibactin is a hybrid polyketide-nonribosomal peptide genotoxin that causes DNA double-strand breaks and interstrand cross-links in eukaryotic cells, leading to genomic instability [2]. Clinical studies have demonstrated a high prevalence of pks+ E. coli in patients with colorectal cancer (CRC) and inflammatory bowel disease, and a distinct colibactin-induced mutational signature (SBS88) has been identified in human CRC genomes [3]. The biosynthetic pathway involves several enzymes (ClbA-S), with the ClbP peptidase serving as a critical 'prodrug' activator that releases the active toxin [4]. Targeting ClbP with small-molecule inhibitors, such as boronic acid derivatives, represents a promising therapeutic approach to prevent colibactin-mediated DNA damage without killing the bacteria or disrupting the broader microbiome [5]. This strategy aims to mitigate the carcinogenic potential of the gut microbiota in high-risk individuals. Research is ongoing to develop potent and selective inhibitors that can be delivered to the colon to neutralize this specific bacterial threat.

Other names

clb gene clusterColibactin-producing Escherichia colipks+ E. coliColibactin biosynthetic pathway

Inhibition of the ClbP peptidase to prevent the maturation of pre-colibactin into the active genotoxin colibactin.