A combined strategy to simultaneously improve the component of isovalerylspiramycin in a bitespiramycin (4″-O-acylspiramycins) complex and its biological titre

Bitespiramycin is a group of 4″-O-acylated spiramycins with 4″-O-isovalerylspiramycins (ivSp) as the major components. It is a key problem how to selectively enhance the biosynthesis of ivSp components during fermentation process. The addition of isovalerate, a precursor supplier of 4″-side chain of ivSp, enhanced the ivSp content in the bitespiramycin complex, but reduced the biological titre owing to the inhibition of growth. At transition phase between growth stage and production stage, the addition with 2-oxoglutarate (2-OG) elevated the titre of bitespiramycin and took no effect on the composition. Combined feeding of isovalerate and 2-OG gave a marked increase in ivSp content accompanied a lift of biological titre. These results suggest that the combined use of the precursor provider and the regulator of carbon metabolism was a successful and cost-effective approach to achieve the balance of biosynthesis of bitespiramycin in terms of composition and titre.