Monique Ponelle

Microbial conversion of rapamycin

Abstract In order to obtain derivatives of rapamycin, a total of 28 bacterial and 72 fungal strains were screened for their ability to transform rapamycin. In the course of this screening, the already known derivatives 39-o-demethylrapamycin, 27-o-demethylrapamycin, 16-o-demethylrapamycin, and the 40-o-phosphoric ester of rapamycin were detected and isolated out of fermentations with Streptomyces rimosus ATCC 28893 or Thamnidium elegans ATCC 8997. Biotransformation of rapamycin using Syncephalastrum racemosus ATCC 1332B, Gliocladium deliquescens ATCC 10097, or Bacillus subtilis ATCC 55060 yielded the conversion products 24-hydroxyrapamycin, secorapamycin A, B, and C, and 16-o-demethylsecorapamycin B. None of these derivatives exhibited a stronger immunosuppressive effect than the parent compound; however, in the case of 24-hydroxyrapamycin and 40-o-phosphoric ester of rapamycin, a FKBP-binding affinity comparable to rapamycin was observed.

A GLYCOSYLPHOSPHATIDYLINOSITOL-ANCHORING INHIBITOR WITH AN UNUSUAL TETRACARBOCYCLIC SESTERTERPENE SKELETON FROM THE FUNGUS CODINAEA SIMPLEX

A novel sesterterpene, YW3699, was isolated from fermentation of the fungus Codinaea simplex. Based on spectroscopic evidence, including UV, IR, FAB-MS, ESI-HRMS, 1H and 13C NMR, DQ-COSY, HQSC and HMBC, YW3699 was shown to have an unusual tetracarbocyclic sesterterpene skeleton. Its relative stereochemistry and solution conformation were elucidated with 1H-1H coupling constants and detailed analysis of its ROESY spectrum, in conjunction with inspection of Dreiding stereomodels. A possible biosynthetic route for YW3699 via the mevalonate pathway is proposed and discussed. YW3699 was found to be an inhibitor of glycosylphosphatidylinositol (GPI) synthesis with a MIC of 3.5 μM.