Abstract

Effect of temperature on synthesis of Clavulanic acid (CA) and impurity substance G during fermentation by Streptomyces clavuligerus were investigated. Results show that fermentation at 24 °C is the most favorable for CA synthesis though the fermentation duration was 20–30 hours longer than fermentation at 26 and 28 °C. Meanwhile, the impurity substance G was only 110 mg/L in the end broth of fermentation at 24 °C, which was significantly lower than 148 and 180 mg/L of fermentation at 26 and 28 °C, respectively. Correlation of specific growth rate and CA synthesis was statistically analyzed based on data of 10 batches of industrial fermentation. Two temperature-shift strategies were investigated in 50 L fermenter. Fermentation with 26–24 °C temperature strategy achieved 5097 mg/L CA titer, meanwhile the fermentation duration was shortened 24 hours comparing with fermentation at constant 24 °C. Fermentation with 26–24 °C control strategy was validated in a 60 m³ industrial fermenter, in which 4960 mg/L of CA was achieved while impurity G substance was decreased to titer 65 mg/L from 200 to 300 mg/L of normal production.

摘要

温度对棒状链霉菌发酵过程中克拉维酸（CA）和杂质G合成的影响进行了调查。结果表明，尽管发酵时间比 26 和 28°C 的发酵时间长 20-30 小时，但 24°C 的发酵最有利于 CA 的合成。同时，24℃发酵终液中杂质G含量仅为110mg/L，明显低于26℃和28℃发酵的148mg/L和180mg/L。以10批次工业发酵数据为基础，对比生长率与CA合成的相关性进行统计分析。在 50 L 发酵罐中研究了两种温度变化策略。采用26-24°C温度策略的发酵达到了5097 mg/L CA滴度，同时与恒定24°C发酵相比，发酵持续时间缩短了24小时。26–24 °C 控制策略的发酵在 60 m³工业发酵罐，其中CA达到4960 mg/L，杂质G物质从正常生产的200-300 mg/L降至65 mg/L。