A Mutasynthesis Approach with a Penicillium chrysogenum ΔroqA Strain Yields New Roquefortine D Analogues

Abstract Penicillium chrysogenum , which lacks the roqA gene, processes synthetic, exogenously added histidyltryptophanyldiketopiperazine (HTD) to yield a set of roquefortine‐based secondary metabolites also produced by the wild‐type strain. Feeding a number of synthetic HTD analogues to the Δ roqA strain gives rise to the biosynthesis of a number of new roquefortine D derivatives, depending on the nature of the synthetic HTD added. Besides delivering semisynthetic roquefortine analogues, the mutasynthesis studies presented here also shed light on the substrate preferences and molecular mechanisms employed by the roquefortine C/D biosynthesis gene cluster, knowledge that may be tapped for the future development of more complex semisynthetic roquefortine‐based secondary metabolites.