Abstract

Background: Tacrolimus, an immunosuppressive calcineurin inhibitor, is widely used in transplantation, as well as in dermatology and invasive cardiology. This drug, first discovered as the product of Streptomyces tsukubaensis, is isolated from the whole fermentation broth of these bacteria cultivated in submerged culture strain. The aim of our research was to optimize the process of tacrolimus biosynthesis by means of submerged cultivation using liquid media containing by or waste- products of food industry. The next goal was to examine the influence of C3 effectors such as propanol, propylene glycol and propionic acid on productivity of the biosynthesis process.
Materials/Methods: The Streptomyces tsukubaensis strain (FERM BP-927) was used to investigate the relationships between the composition of the cultivation medium, the mycelial growth and tacrolimus production. Furthermore, the cultures were enriched with propanol, propylene glycol and propionic acid, used as biosynthesis precursors.
Results: The productivity of tacrolimus by the strain is proportional to the mycelial growth. The highest productivity recorded for medium composed in-part of waste products of food industry and not enriched in precursors was approximately 12 μg/mL, and thus approximates the productivity declared in Okuhara et al's US patent. The addition of the biosynthesis precursors, propanol, propylene glycol and propionic acid results in about 3-fold higher biosynthesis productivity. The highest productivity was obtained when
propylene glycol was used.
Conclusions: There is a strong correlation between the composition of the tested media and the strain productivity. Propanol, propylene glycol and propionic acid exert an inducing effect on tacrolimus biosynthesis.

Keywords: Tacrolimus, P. mirabilis, propanol