Biosynthesis of Tacrolimus by the Streptomyces tsukubensis VKM Ac-2618D Strainin the Presence of Polymeric Sorbents and Development of a Method for Its Isolation and Purification
Tacrolimus is known as one of the most effective immunosuppressive agents. This macrocyclic polyketide is synthesized by actinobacteria of the genus Streptomyces, however, the process is accompanied by the undesirable formation of close structural analogues. For now, the problem of the efficient isolation and purification of tacrolimus according to the requirements of pharmacopeia is still unsolved. An original method of tacrolimus biosynthesis by the actinobacterial strain Streptomyces tsukubensis VKM Ac-2618D using brominated styrene-divinylbenzene sorbent SP-207 was developed. This approach allowed to reduce the undesirable destruction of tacrolimus, increase its yield and simplifying the isolation procedure from the culture medium. The preliminary purification stage was optimized by utilization of regenerated sorbents based on methyl methacrylate (HP2MG) and chemically modified silica gel (Diasorb-100-Diol). The implementation of the silica gel sorbents with grafted sulfonic groups modified with silver ions at the finishing purification step allowed significantly increase the productivity of this key stage. The yield of tacrolimus according to the developed method was around 60–70%. The results could be implemented for the full-cycle production development of the pharmaceutical grade tacrolimus.