响应面法优化他克莫司发酵培养基中无机盐组合  

Optimization of inorganic salts of fermentation medium for tacrolimus production by response surface methodology

作　　者：严凌斌[1] 张祝兰[1] 张引[1] 陈洲琴 王德森[1,2] 连云阳 Yan Ling-bin;Zhang Zhu-lan;Zhang Yin;Chen Zhou-qin;Wang De-sen;Lian Yun-yang(Fujian Provincial Key Laboratory of Screening for Novel Microbial Products,Fujian Institute of Microbiology,Fuzhou 350007;Fujian Kerui Pharmaceutical Co.,Ltd.,Fuzhou 350313)

机构地区：[1]福建省微生物研究所福建省新药(微生物)筛选重点实验室,福州350007 [2]福建科瑞药业有限公司,福州350313

出　　处：《中国抗生素杂志》2020年第10期994-999,共6页Chinese Journal of Antibiotics

基　　金：福建省属公益类研究所基本科研专项(No.2019R1005-8);福州市科技计划项目(No.2018-G-48);福清市科技计划项目[No.融科2018(6)]。

摘　　要：目的利用响应面法优化发酵培养基中的无机盐成分,提高他克莫司产量。方法在单因素实验的基础上,利用Plackett-Burman设计筛选对他克莫司产量有显著影响的无机盐因子,利用最陡爬坡试验为响应面分析确定中心区域,利用中心组合(central composite)设计与响应面分析法获得关键因素的最佳浓度组合。结果磷酸氢二钾、硫酸铜、氯化钠和硫酸镁对他克莫司的产量有显著影响,最优无机盐组成为:磷酸氢二钾2g/L,硫酸铜0.02g/L,氯化钠1.81g/L,硫酸镁0.82g/L,在原有培养基上添加该无机盐最优组合,他克莫司产量从586mg/L上升到1037mg/L。与优化前培养基相比,产量提高了77.0%。结论经响应面法优化,添加最优无机盐组合使他克莫司产量得到显著的提高。Objective To enhance the tacrolimus production,the effects of inorganic salts of fermentation medium on tacrolimus production were studied by response surface methodology.Methods Plackett-Burman design was used to select key factors of inorganic salts for tacrolimus production.The steepest ascent method was used to determine the optimal range of values and confirm the central axis.Central composite design was used to confirm the optimal concentration of the key factors.Results In accordance with Plackett-Burman design,the most significant positive independent variables of inorganic salts affecting tacrolimus production were found to be K2HPO4,CuSO4,NaCl and MgSO4.Central composite design and response surface methodology were chosen to elucidate the mutual interactions between the variables and identify the optimum variables on metabolite production.It was found that,with the optimized conditions of K2HPO42g/L,CuSO40.02g/L,NaCl 1.81g/L,MgSO40.82g/L,tacrolimus production increased 77.0%(from 586 to 1,037mg/L in a shake-flask).Conclusion Under the optimal conditions of inorganic salts combination,the tacrolimus production was significantly enhanced.

关 键 词：链霉菌 他克莫司 发酵培养基 响应面法 无机盐 

分 类 号：R978.1[医药卫生—药品] TQ465.92[医药卫生—药学]