Biosynthesis of the Fungal Cyclic Lipodepsipeptide Pleosporacin, a New Selective Inhibitor of the Phytopathogen Botrytis cinerea

Bioactivity-guided isolation led to the identification of the cyclic lipodepsipeptide pleosporacin (1) from the mycelia extract of fungal strain Pleosporales sp. IBWF 020-21, a potent selective inhibitor of the fungal phytopathogen Botrytis cinerea. The structure and stereochemistry of 1 were elucidated by NMR and Marfey analysis, respectively. Genome mining identified a candidate biosynthetic gene cluster encoding a hexamodular nonribosomal peptide synthetases, PleA, a fatty acyl-AMP ligase, PleB, and an aspartate decarboxylase, PleC. Reconstitution of pleABC allowed for heterologous production of 1 in Aspergillus oryzae and confirmed the identity of the ple cluster. Based on these findings a biosynthetic route is proposed, with PleB catalyzing lipoinitiation and PleC providing the nonproteinogenic amino acid β-alanine for the assembly of 1.