Exploration of the Substrate Promiscuity of Biosynthetic Tailoring Enzymes as a New Source of Structural Diversity for Polyene Macrolide Antifungals

• Published in: ChemCatChem 2015-02, Vol.7 (3), p.490-500
• Main Authors: Santos-Aberturas, Javier, Engel, Jennifer, Dickerhoff, Jonathan, Dörr, Mark, Rudroff, Florian, Weisz, Klaus, Bornscheuer, Uwe T.
• Format: Article
• Language: English
• Subjects: antibiotics; antifungal agents; chemical diversity; Cytochrome; Enzymes; natural products; P450 cytochromes
• ISSN: 1867-3880; 1867-3899
• DOI: 10.1002/cctc.201402773

Even though there is an urgent need for new antifungals with improved clinical properties, the substrate promiscuity of tailoring enzymes has been poorly studied as a source of new structural diversity for polyene macrolides. We explore the acceptance of different polyene macrolides by the glutamine amidotransferase PscA and the catalytic effect of different homologous P450 cytochromes on a common scaffold, the pimaricin precursor 4,5‐desepoxypimaricin. By combining these two parallel strategies, we present three new pimaricin derivatives and a new lucensomycin variant. Our results show that P450 cytochromes devoted to the modification of the polyol region of polyene macrolides are not as substrate‐specific as previously thought and highlight PscA as a versatile small‐ring polyene‐modifying enzyme that allows the preparation of new carboxamide derivatives. We also provide useful information for the future production of previously unconceived epoxidized polyene macrolide antifungals. Promise of promiscuity: The substrate promiscuity of two groups of biosynthetic tailoring enzymes opens up new perspectives for the creation of new valuable polyene macrolide antifungals. New hydroxylated and carboxamidated derivatives are described and possible epoxidations suggested.