The mechanism by which the genotoxin Colibactin triggers microbial population resistance

By | November Colibactin is a chemically unstable small-molecule genotoxin produced by several different bacteria, including human gut microbes, whose synthesis relies on the 54kb-sized ribosomal polypeptide synthase-poly Keto synthase biosynthetic gene cluster, this region is called pks island (Fig.
1) [1,2]
.

Colibactin has been extensively studied in humans, etc.
, as this metabolite induces DNA interstrand crosslinks in vitro, causes cell cycle arrest in eukaryotic cell culture, and promotes tumor formation in mouse models of colorectal cancer 【3】
.

But the effects of Colibactin on microbial communities compared to eukaryotes are unknown
.

Fig.
1 Genotoxin Colibactin and pks island Recently, the research group of Emily P.
Balskus at Harvard University published an article The bacterial toxin colibactin triggers prophage induction in Nature.
Resistant and protective effects occur to protect bacteria from this genotoxin, the resistance genes of Colibactin and the mechanisms by which microbial products influence the microbial community were identified
.

The study began because of multiple lines of evidence that other bacteria suffer from DNA damage mediated by the Colibactin genotoxin
.

Different self-resistance mechanisms are encoded in bacteria, suggesting that Colibactin, like many toxic bacterial natural products, is harmful to other bacteria
.

But by mixing Colibactin-producing bacteria 1:1 with non-colibactin-producing bacteria, the authors found that the growth of non-colibactin-producing bacteria was not significantly affected
.

So what are the effects of the genotoxin Colibactin on other microbial communities? The authors speculate that it may be prophage induction, since studies have shown that UV light and chemical agents can cause the activation of phages in bacteria, killing cells and creating hazards in the wider microbial community [4]
.

Prophages are a latent form of phage infection that incorporate phage nucleic acid into bacteria
.

The authors therefore wondered whether Colibactin could affect bacterial communities by activating prophages
.

To test this possibility, the authors infected wild-type E.
coli with phage and co-cultured with pks+ or pks- E.
coli
.

The results suggest that Colibactin specifically affects bacteria by inducing prophages, and that this process is dependent on cell-to-cell contact and phage receptor genes in bacteria
.

The authors then wanted to further expand the detection of the genotoxic effects of Colibactin, so pks+ or pks- E.
coli were co-cultured with a variety of prophage-carrying intestinal strains
.

The authors found that Colibactin induced relevant prophage responses in humans, whether in a co-culture environment in vitro or in a close-in vivo gut microbial environment
.

In addition, the authors' results show that pks- strains develop Colibactin resistance, and the authors would like to know the specific molecular mechanism
.

Through bioinformatics search, the authors found that the self-resistance protein ClbS in E.
coli provides bacteria with a protective umbrella against Colibactin, and the specific mechanism of this resistance process is to promote phage genome silencing
.

Colibactin, a complex natural product produced by gut bacteria, has a wide range of biological targets and results in pathogenicity
.

But the genotoxin's effect on the microbial population has not been known until now
.

By prophage-inducing activity of Colibactin-producing bacteria against other bacteria, the authors uncovered a new mechanism by which natural products such as Colibactin that may damage DNA can shape microbial communities
.

In addition, this mechanism provides a unique idea for the treatment of various tumors, because non-colibactin-producing strains will develop resistance mechanisms to protect the microbial community, which lays the foundation for further studies on how bacterial metabolites regulate phage behavior and affect human diseases.
foundation
.

Original link: https://doi.
org/10.
1038/s41586-022-04444-3 Publisher: Eleven References 1.
Nougayrède, J.
-P.
et al.
Escherichia coli induces DNA double-strand breaks in eukaryotic cells .
Science 313, 848–851 (2006).
2.
Auvray, F.
et al.
Insights into the acquisition of the pks island and production of colibactin in the Escherichia coli population.
Microb.
Genomics 7, 000579 (2021).
3.
Dougherty, MW & Jobin, C.
Shining a light on colibactin biology.
Toxins 13, 346 (2021).
4.
Ofir, G.
& Sorek, R.
Contemporary phage biology: from classic models to new insights.
Cell 172, 1260– 1270 (2018) Reprint Notice [Original Article] BioArt original article, welcome to forward and share, and reprint is prohibited without permission.
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