Colibactin is a potent genotoxin that induces DNA double-strand breaks; it is produced by Escherichia coli strains harboring a pks+ island. It has been ten years since the discovery of this pks+ island (the colibactin biosynthetic gene cluster). The pathogenicity and the underlying mechanisms of these pks+ strains are in the process of being elucidated. However, the precise chemical structure of colibactin remains elusive, which severely hampers attempts to acquire an in-depth understanding of this compound.

Here, using transformation-associated recombination (TAR) cloning to perform heterologous expression, I took advantage of the significantly increased yield of colibactin pathway-related compounds to determine and isolate a series of vital (pre)colibactin intermediates....[ Read more ]

Colibactin is a potent genotoxin that induces DNA double-strand breaks; it is produced by Escherichia coli strains harboring a pks+ island. It has been ten years since the discovery of this pks+ island (the colibactin biosynthetic gene cluster). The pathogenicity and the underlying mechanisms of these pks+ strains are in the process of being elucidated. However, the precise chemical structure of colibactin remains elusive, which severely hampers attempts to acquire an in-depth understanding of this compound.

Here, using transformation-associated recombination (TAR) cloning to perform heterologous expression, I took advantage of the significantly increased yield of colibactin pathway-related compounds to determine and isolate a series of vital (pre)colibactin intermediates. The chemical structures of compounds 8, 10 and 11 were identified by NMR and MSⁿ analyses.

The novel 1H-pyrrolo[3,4-c]pyridine-3,6(2H,5H)-dione- and thiazole-containing 10 provides new insights regarding the biosynthetic pathway to (pre)colibactin and establishes foundations for future investigation of the intriguing (pre)colibactin structures and its modes of action.