Objective

This study was conducted to enhance the production of tacrolimus in Streptomyces tsukubaensis by strain mutagenesis and optimization of the fermentation medium.

Results

A high tacrolimus producing strain S. tsukubaensis FIM-16-06 was obtained by ultraviolet mutagenesis coupled with atmospheric and room temperature plasma mutagenesis.Then, nine variables were screened using Plackett–Burman experimental design, in which soluble starch, peptone and Tween 80 showed significantly affected tacrolimus production. Further studies were carried out employing central composite design to elucidate the mutual interaction between the variables and to work out optimal fermentation medium composition for tacrolimus production. The optimum fermentation medium was found to contain 61.61 g/L of soluble starch, 20.61 g/L of peptone and 30.79 g/L of Tween 80. In the optimized medium, the production of tacrolimus reached 1293 mg/L in shake-flask culture, and reached 1522 mg/L while the scaled-up fermentation was conducted in a 1000 L fermenter, which was about 3.7 times higher than that in the original medium.

Conclusions

Combining compound mutation with rational medium optimization is an effective approach for improving tacrolimus production, and the optimized fermentation medium could be efficiently used for industrial production.

中文翻译：

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Plackett-Burman 设计结合响应面法通过诱变和优化发酵培养基提高筑波链霉菌他克莫司产量

客观的

本研究旨在通过菌株诱变和发酵培养基优化提高筑波链霉菌中他克莫司的产量。

结果

一种高产他克莫司的菌株S. tsukubaensisFIM-16-06是通过紫外诱变结合大气和室温等离子体诱变获得的。然后，使用Plackett-Burman实验设计筛选了9个变量，其中可溶性淀粉、蛋白胨和吐温80对他克莫司的产量有显着影响。采用中心复合设计进行了进一步的研究，以阐明变量之间的相互作用，并制定出生产他克莫司的最佳发酵培养基组成。最佳发酵培养基中可溶性淀粉61.61 g/L、蛋白胨20.61 g/L、吐温80 30.79 g/L。在优化后的培养基中，他克莫司在摇瓶培养中的产量达到1293 mg/L , 在 1000 L 发酵罐中进行放大发酵时达到 1522 mg/L，约为 3。

结论

将复合突变与合理培养基优化相结合是提高他克莫司产量的有效途径，优化后的发酵培养基可有效用于工业化生产。