MICROBIAL BIOTRANSFORMATION PRODUCTS OF CYCLOSPORINE-A

In order to mimic the human metabolic pathway of cyclosporin A (CyA) a total of 28 bacterial and 72 fungal strains was screened for their ab ility to transform CyA. Among 3 bacteria and 11 fungi, which produced the main human metabolite OL-17 [nHyMeBmt(1)]CyA, Actimoplanes sp. (AT CC 53771) achieved the best transformation rate (5.4%). Furthermore, t he two N-demethylated minor products [Leu(4)]CyA (3.2%) and [Leu(9)]Cy A (4.7%) were isolated both known as minor natural metabolites and the first one also as a human biotransformation product. Microbial conver sion-of CyA using the actinomycete Sebekia benihana (NRRL 11111) yield ed [gamma HyMeLeu(4)]CyA (35%), [gamma HyLeu(4)]CyA (4.5%) and [gamma HyMeLeu(4), gamma HyMeLeu(6)]CyA (8.6%). The structures of these deriv atives correspond with those of the human metabolic pathway. The;elate d compounds [Nva(2)]CyA (CyG) and [D-MeSer(3)]CyA were similarly conve rted to the corresponding 4-gamma-hydroxylated analogues, None of the biotransformation products showed a better immunosuppressive effect th an CyA, although in various cases the cyclophilin binding affinity was comparable to that of CyA.