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.