Abstract
Colibactin is a polyketide/nonribosomal peptide produced by Escherichia coli strains that harbor the pks island. This toxin induces DNA double-strand breaks and DNA interstrand cross-links in infected eukaryotic cells. Colibactin-producing strains are found associated with colorectal cancer biopsy specimens and promote intestinal tumor progression in various murine models. Polyamines are small polycationic molecules produced by both microorganisms and eukaryotic cells. Their levels are increased in malignancies, where they contribute to disease progression and metastasis. In this study, we demonstrated that the endogenous spermidine synthase SpeE is required for full genotoxic activity of colibactin-producing E. coli Supplying spermidine in a ΔspeE pks+E. coli strain restored genotoxic activity. Spermidine is involved in the autotoxicity linked to colibactin and is required for direct damaging activity on DNA. The production of the colibactin prodrug motif is impaired in ΔspeE mutants. Therefore, we demonstrated that spermidine has a direct impact on colibactin synthesis.IMPORTANCE Colibactin-producing Escherichia coli strains are associated with cancerous and precancerous colorectal tissues and are suspected of promoting colorectal carcinogenesis. In this study, we describe a new interplay between the synthesis of the genotoxin colibactin and the polyamine spermidine. Polyamines are highly abundant in cancer tissue and are associated with cell proliferation. The need for spermidine in genotoxic activity provides a new perspective on the role of these metabolites in the pathogenicity of colibactin-producing E. coli strains in colorectal cancer.
Highlights
Colibactin is a polyketide/nonribosomal peptide produced by Escherichia coli strains that harbor the pks island
To test the impact of the endogenous spermidineputrescine pathway on colibactin-producing E. coli genotoxic activity, mutants inactivated for the speB, speC, speE, and speG genes (Fig. 1A) were engineered in E. coli strain DH10B, which harbors the pks island on a bacterial artificial chromosome (Table 1) [34]
The inactivation of speE in pksϩ E. coli from other genetic backgrounds resulted in a decrease in the megalocytosis effect (Table 1 and Fig. 1C)
Summary
Colibactin is a polyketide/nonribosomal peptide produced by Escherichia coli strains that harbor the pks island. This toxin induces DNA double-strand breaks and DNA interstrand cross-links in infected eukaryotic cells. The need for spermidine in genotoxic activity provides a new perspective on the role of these metabolites in the pathogenicity of colibactin-producing E. coli strains in colorectal cancer. An association between colibactin-producing E. coli and enterotoxigenic Bacteroides fragilis, another procarcinogenic bacterial species, was noted on the colonic mucosa of patients with familial adenomatous polyposis (FAP), who are highly susceptible to colorectal cancer [20]. A synergy between these two bacterial species was observed in tumor formation in an FAP murine model [20]
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