Biosynthesis and bioactivities of microbial genotoxin colibactins

Abstract

This review provides an update on biosynthesis and bioactivities of colibactin(s), the long-sought genotoxins produced by the pks island of Escherichia coli.

Advancing the Biosynthetic and Chemical Understanding of the Carcinogenic Risk Factor Colibactin and Its Producers

“…It is thought that colibactin was so recalcitrant to structural characterization primarily because it is chemically too unstable to exist within the producing bacteria in large quantities or to withstand the isolation and purification processes to prepare it in high yield. 17,18 Therefore, many studies focused on characterizing metabolites that were considered to be derived from the intact colibactin, especially DNA adducts, and attempted to reconstruct the intact structure of colibactin on the basis of the available biochemical and biosynthetic knowledge (reviewed in detail recently 19 ). It was not until 2019 that the structure of intact colibactin began to emerge.…”

“…Despite the identification of the clb cluster, elucidation of the chemical structure of the mature colibactin remained unsuccessful after attempts by many research groups for more than 10 years. It is thought that colibactin was so recalcitrant to structural characterization primarily because it is chemically too unstable to exist within the producing bacteria in large quantities or to withstand the isolation and purification processes to prepare it in high yield. , Therefore, many studies focused on characterizing metabolites that were considered to be derived from the intact colibactin, especially DNA adducts, and attempted to reconstruct the intact structure of colibactin on the basis of the available biochemical and biosynthetic knowledge (reviewed in detail recently). It was not until 2019 that the structure of intact colibactin began to emerge. − Research on the mechanism by which colibactin induces colorectal cancer is making steady progress, and the importance of colibactin as a risk factor for colorectal cancer is increasing. − Our group has also conducted research on elucidating the structure of colibactin.…”

The microbiome-product colibactin hits unique cellular targets mediating host–microbe interaction

“…The cluster consisted of 19 genes, named alphabetically, clb A-S. These 19 genes encode three polyketide synthases (PKSs), three nonribosomal peptide synthases (NRPSs), two hybrids NRPS/PKS, MATE transporter, resistance gene, and other nine tailoring and accessory enzymes as per the latest update as reviewed ( Tang et al, 2022 ). Intensive research reports confirm that all of these genes are essential for genotoxicity, except for clb M, S, and R ( Nougayrède et al, 2006 ).…”

“…Isolation and structural elucidation of colibactin has challenged the scientific field for over 15 years because of its contact-dependent synthesis, minimal expression, and chemical instability. The bulk of the research study on colibactin is centered around revealing its structure, mainly through bioinformatic analysis, comparative metabolomics, and mutational studies ( Tang et al, 2022 ). However, to appreciate the evolved function of colibactin(s) and other microbiome products, we must understand their ecological role in enhancing the competency and fitness of producers.…”

“…Our knowledge of colibactin(s) is developing and there are previous reviews covering their prospective research period ( Faïs et al, 2018 ; Bode 2015 ; Balskus 2015 ; Williams et al, 2020 ; Wernke et al, 2020 ; Tang et al, 2022 ). These reviews mainly focused on summarizing advances in understanding possible biosynthetic pathways, bioinformatic prediction of colibactin and precolibactin structures, and the mechanism of DNA mutation.…”