子囊霉素生产菌种的选育及发酵优化  

Breeding and Fermentation Optimization of Ascomycin Producing Strains

作　　者：刘倩倩 吴远杰[2] 张正玉 陈少欣[2] LIU Qianqian;WU Yuanjie;ZHANG Zhengyu;CHEN Shaoxin(School of Chemistry and Chemical Engineering,Shanghai University of Engineering Science,Shanghai 201620;State Key Lab.of New Drug and Pharmaceutical Process,Shanghai Institute of Pharmaceutical Industry,China State Institute of Pharmaceutical Industry,Shanghai 201203)

机构地区：[1]上海工程技术大学化学化工学院,上海201620 [2]中国医药工业研究总院,上海医药工业研究院,创新药物与制药工艺国家重点实验室,上海201203

出　　处：《中国医药工业杂志》2022年第6期842-848,共7页Chinese Journal of Pharmaceuticals

摘　　要：子囊霉素(ascomycin,FK520)是由吸水链霉菌(Streptomyces hygroscopicus)发酵产生的大环内酯类抗菌药,有多种生物活性,具有重要药学应用价值。为了实现FK520的规模化发酵生产,本研究以吸水链霉菌SFK-6-33(2.43 g/L)为出发菌株,通过自然分离、诱变选育和基因改造,获得了高产突变菌株SFK-OASN-N3-25(2.92 g/L),产量较出发菌株提高了20.16%。进一步在5 L发酵罐研究中进行分批补料培养,通过优化甘油补料浓度和pH值,确定甘油补加量为2.5%、pH控制在5.6以上为最佳发酵条件。采用优化后的发酵工艺,FK520产量能达到4.64 g/L,为目前报道最高产量。最后,通过3批发酵试验验证了FK520发酵单位为4.66~4.97 g/L,为规模化发酵FK520奠定了基础。Ascomycin(FK520) is a macrolides antibiotic produced by Streptomyces hygroscopicus.It has a variety of biological activities and with a high application value.In order to realize the large-scale fermentation production of FK520,in this study,the high-yielding mutation strain SFK-OASN-N3-25(2.92 g/L) was obtained from SFK-6-33(2.43 g/L) through natural isolation,mutation breeding,and genetic modification,and the yield was 20.16% higher than that of the original strain.Then the fed-batch culture was carried out in a 5 L fermenter to optimize the glycerol supplemental concentration and pH.It was determined that the optimal fed-batch culture conditions were as follows:glycerol supplemental concentration was 2.5%,and the pH was controlled above 5.6.In the optimized fermentation process,the yield of FK520 reached 4.64 g/L,which is the highest yield reported at present.Finally,the fermentation yields of FK520 were 4.66-4.97 g/L through three batches of fermentation verification,which laid a foundation for large-scale fermentation of FK520.

关 键 词：吸水链霉菌 子囊霉素 菌种改造 发酵 工艺优化 

分 类 号：R939.97[医药卫生—生药学]