Hybrid biosynthesis of derivatives of protylonolide and M-4365 by macrolide-producing microorganisms

Biotransformation of a macrolide antibiotic and a related compound was studied using various macrolide-producing microorganisms grown in the presence of cerulenin, an inhibitor of de novo synthesis of the aglycone moiety. Protylonolide (1) was transformed into 5-O-(4'-O-propionylmycarosyl)protylonolide (2) by a leucomycin-producing strain, Streptoverticillium kitasatoensis KA-429. M-4365 G2 (3) was bioconverted into M-4365 G3 (4), 9-dihydro M-4365 G3 (5), 3-O-acetyl M-4365 G3 (6) and 3-O-acetyl-9-dihydro M-4365 G3 (7) by a spiramycin-producing strain, Streptomyces ambofaciens KA-1028. Forosaminylated derivatives of M-4365 G2 were not obtained using this microorganism. M-4365 G2 was converted into 3-O-acetyl M-4365 G2 (8) by Stv. kitasatoensis strain KA-429 and a carbomycin-producing strain, S. thermotolerans KA-442. These results suggest that the substrate specificity of mycaminose- and forosamine-binding enzymes is high in Stv. kitasatoensis and S. ambofaciens, respectively, while that of the 3-hydroxyl acylating enzyme and mycarose-binding enzyme is low in these microorganisms. The bioconversion products showed lower antibacterial and antimycoplasmal activities than those of M-4365 G2.