The pneumocandin family of antifungal drugs – Update on biodiversity and biosynthesis

The pneumocandins are a subset of the echinocandin class of antifungal drugs that control human invasive fungi by non-competitively inhibiting 1,3-β-glucan synthase, a membrane-bound enzyme responsible for the main structural polymer of the fungal cell wall. Among the echinocandin lipopeptides, pneumocandins, including sporiofungin and FR190293, are distinguished by a hydroxy-glutamine at the 5^th residue in the core peptide and an acyl side chain originating from a highly-reducing PKS. The reactions of most of the catalytic enzymes in the pathways have been elucidated by functional analyses. Our lab has inactivated pathway oxidation and lipoinitiation reactions to generate new pneumocandin analogues and has explored the effects of deletion of putative type II thioesterase on efficiency of pneumocandin synthesis. Availability of these analogues afforded an opportunity for side-by-side exploration of the effects of hydroxylation and lipid side chain substitutions on pneumocandin antifungal activity and enabled the discovery of some analogues more potent in vitro against Candida species than the parent natural products. We have also observed a general pattern indicating that echinocandin-producing Aspergilli are sensitive to echinocandins, while echinocandin-producing fungi of the Leotiomycetes tend to be self-resistant to their products. Elucidation of the sporiofungin gene cluster revealed an unusual FKS1-like gene immediately upstream. Its inactivation dramatically increased self-sensitivity to echinocandins, indicating that it may be a self-resistance gene. The relationships between gene clusters, chemical structural complexity, and innate self-resistance provide a framework for developing hypotheses about the natural functions of these cell-wall-active lipopeptides.