Clavulanic acid (CA) is a naturally occurring antibiotic produced by Streptomyces clavuligerus. Statistical optimization of the fermentation medium for CA production by Streptomyces clavuligerus was carried out. Multiple carbon sources, glycerol, dextrin, and triolein, were considered simultaneously. A two-level fractional factorial design experiment was conducted to identify the significant components of medium on CA production. Statistical analysis of the results showed that soybean meal, dextrin, and triolein were the most significant medium ingredients on CA production. The optimal level of these screened components was obtained by RSM based on the result of a Box-Behnken design, in which the values of dextrin, soybean meal, and triolein in CA fermentation medium were 12.37 g/L, 39.75 g/L, and 26.98 ml/L, respectively. Using the proposed optimized medium, the model predicted 938 mg/L of CA level and via experimental rechecking the model, 946 mg/L of CA level was attained in shake flask fermentation, significantly high than 630 mg/L of original medium. The optimized medium was further verified in 50-L stirred fermenter, and compared with performance of original medium in parallel, CA titer was increased from 889 to 1310 mg/L; a 47% increase was achieved through medium optimization by statistical approaches.

克拉维酸 (CA) 是一种由Streptomyces clavuligerus产生的天然抗生素。对Streptomyces clavuligerus生产CA的发酵培养基进行了统计优化。同时考虑了多种碳源，甘油、糊精和三油精。进行了两水平部分因子设计实验，以确定培养基对 CA 生产的重要成分。结果的统计分析表明，豆粕、糊精和三油精是影响CA生产的最重要的培养基成分。这些筛选组分的最佳水平是通过 RSM 基于 Box-Behnken 设计的结果获得的，其中 CA 发酵培养基中糊精、豆粕和三油精的值分别为 12.37 g/L、39.75 g/L 和分别为 26.98 毫升/升。使用所提出的优化培养基，模型预测CA水平为938 mg/L，通过实验复核模型，摇瓶发酵达到946 mg/L CA水平，显着高于原始培养基的630 mg/L。优化后的培养基在50L搅拌发酵罐中进一步验证，与平行原培养基相比，CA滴度从889提高到1310 mg/L；通过统计方法的介质优化实现了 47% 的增长。