Critical Intermediates Reveal New Biosynthetic Events in the Enigmatic Colibactin Pathway

ChemBioChem
2015.0

Abstract

<jats:title>Abstract</jats:title><jats:p>Colibactin is a potent genotoxin that induces DNA double‐strand breaks; it is produced by <jats:italic>Escherichia coli</jats:italic> strains harboring a <jats:italic>pks</jats:italic>+ island. However, the structure of this compound remains elusive. Here, using transformation‐associated recombination (TAR) cloning to perform heterologous expression, we 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 <jats:bold>8</jats:bold>, <jats:bold>10</jats:bold> and <jats:bold>11</jats:bold> were identified by NMR and MS<jats:sup><jats:italic>n</jats:italic></jats:sup> analyses. The new 1<jats:italic>H</jats:italic>‐pyrrolo[3,4‐<jats:italic>c</jats:italic>]pyridine‐3,6(2<jats:italic>H</jats:italic>,5<jats:italic>H</jats:italic>)‐dione‐ and thiazole‐containing compound <jats:bold>10</jats:bold> 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.

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