Abstract
Rapamycin, a metabolite of Streptomyces hygroscopicus, has a wide range of therapeutic applications in medicine. However, the possibility of its use is significantly limited, since the existing natural strains of this microorganism have rather low productivity that negatively influences the cost of the substance and the possible volumes of its industrial production. At the same time, the commercial use of overproducing strains is also very problematic, since they secrete a large number of metabolites suppressing both the growth of microbial culture and the biosynthesis of a target product. A possible way to solve the problem includes the addition of adsorbents to a fermentation medium for the binding of excess metabolites. In this study, five different selective adsorbing resins, DIAION™ HP20, DIAION™ HP21, DIAION™ HP 20SS, Chromolite, and LPS-500 were tested to provide optimal conditions for the rapamycin biosynthesis by the earlier developed highly-active S. hygroscopicus strain VKM Ac-2737D. The experiments were performed in a 15-L bioreactor using the optimized fermentation medium developed earlier and supplemented with the tested resins. The highest rapamycin yield (1420±5 mg/L) was obtained using a Chromolite 15AD2 adsorbing resin; this result exceeds the earlier obtained yield by 11.4%. The sorptive capacity of this resin was 92% that may significantly facilitate the processes of rapamycin isolation and purification under industrial conditions. The results of the study may be of certain interest for the further scaling-up of the industrial rapamycin production.
Highlights
Rapamycin, which is known as sirolimus, is a secondary metabolite of the actinomycete bacterium Streptomyces hygroscopicus (Vezina et al, 1975)
Taking into account a high need in the efficient rapamycin production technology suitable for a large-scale realization, the purpose of this study was the selection of a selective adsorbing resin providing optimal conditions for the rapamycin biosynthesis by S. hygroscopicus ВКМ Ac-2737D
In this study the Streptomyces hygroscopicus strain VKM Ас-2737D obtained from the initial S. hygroscopicus strain ATCC 29253 by a multi-step selection combined with the use of mutagenic factors and the directed selection and deposited in the All-Russian Collection of Microorganisms was used
Summary
Rapamycin, which is known as sirolimus, is a secondary metabolite of the actinomycete bacterium Streptomyces hygroscopicus (Vezina et al, 1975). Some researchers consider rapamycin as a remedy for delaying aging and for prevention and therapy of age-associated diseases, such as atherosclerosis, osteoarthritis, neurodegenerative ad heart diseases (Blagosklonny, 2017; Bagherpour et al, 2018). Everolimus actively inhibits the growth and proliferation of fibroblasts, as well as the tumor, endothelial, and unstriated muscle tissues of blood vessels and is considered a promising drug for the therapy of a progressive hormone-dependent HER2-negative breast cancer in women in a post-menopause period and the therapy of adult patients suffering from the renal angiomyolipoma, nonfunctional neuroendocrinal tumors of the gastrointestinal or pulmonary origin, and progressive neuroendocrinal tumors of the pancreas (Chan et al, 2010; Hasskarl, 2018)
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