Improving and diversifying the production and investigating the biosynthesis of phomactins by the cultured fungus Biatriospora sp. CBMAI 1333

Abstract

Phomactins are fungal natural products known to inhibit the platelet activating factor receptor (PAFR). Phomactins have also been shown to reduce the repopulation of tumor cells after radiation therapy, suggesting that these molecules could be used as adjuvants in cancer therapy. Phomactins are chemically complex diterpenes that share homology with the taxane family of compounds. To date, only four fungal strains have been described to produce phomactins, including the marine fungal strain Biatriospora sp. CBMAI 1333. Total syntheses approaches have been developed for the phomactins; however, these are still complex, multi-step processes. Therefore, production via fermentation is a method of choice for obtaining these compounds. Additionally, the biosynthesis of phomactins has been addressed only by using 13C-labeled precursors and no gene clusters have been associated to phomactin biosynthesis. The first aim of this research proposal is to apply comparative metabolomics based on liquid chromatography-mass spectrometry (LC-MS) to analyze Biatriospora sp. CBMAI 1333 growing on various culture conditions. This approach will allow the identification of culture conditions inducing maximum production and diversification of phomactins. The second aim involves genome sequencing and genome mining to determine the genes responsible for the biosynthesis of phomactins. Knock-out mutants will be produced to confirm the association of candidate genes with phomactin biosynthesis.