博莱霉素发酵培养基及发酵条件优化研究
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摘要
博莱霉素(Bleomycin)是从轮枝链霉菌(Streptomyces verticillus)发酵产物中发现的具有抗肿瘤活性的多组分糖肽类抗生素,各组分区别在于末端胺的不同。博莱霉素是广谱,低毒的抗肿瘤药物,对恶性淋巴瘤、头颈部癌、乳腺癌和食道癌有良好的疗效,还对发病率高,又无有效药物治疗的肝癌有较满意的疗效。因此提高博莱霉素在发酵液中的含量具有非常重要的意义。
从博莱霉素的摇瓶发酵着手,对培养基组成和培养条件进行了优化,并考察了前体加入时间和加入浓度对博莱霉素产量的影响。考察了碳源、有机氮源、无机氮源、磷酸盐和CuSO_4对博莱霉素发酵的影响,确定了最佳发酵培养基配方为:葡萄糖1%,麦芽糖3%,可溶性淀粉3%,大豆蛋白胨0.5%,黄豆饼粉3%,玉米浆1%,豆油0.5%,NaCl 0.3%,K_2HPO_4 0.1%,ZnSO_4 0.05%,CHSO_4 0.01%,NaNO_3 0.3%,优化后的发酵培养基使链霉菌Streptomyces verticillus U-43在摇瓶培养条件下博来霉素的产量达到41.23μg/ml。在对链霉菌Streptomyces verticillus U-43的培养条件优化的过程中,分别考察了接种龄、接种量、发酵培养基初始pH值、摇瓶装液量对发酵的影响,结果表明:链霉菌Streptomyces verticillus U-43的最适接种龄为48h,最佳培养温度为28℃,发酵培养基的最适初始pH为6.0,接种量为6%,摇瓶装液量为80ml/500ml△。经发酵培养条件优化后,链霉菌Streptomyces verticillus U-43在摇瓶培养条件下博莱霉素的产量达到46.11μg/ml。采用优化的发酵培养基配方和发酵条件,并在发酵进行至60h添加0.04mg/ml的前体精胺,可明显提高效价,其摇瓶效价达62.21μg/ml。
以摇瓶发酵实验为基础,进行了博莱霉素发酵由摇瓶到16L发酵罐的放大,考察了轮枝链霉菌(Streptomyces verticillus)U-43在16L发酵罐中的代谢特性,包括发酵过程中的pH、糖代谢、氮代谢、生物量、溶氧、效价,确定了发酵的溶氧临界点不低于20%、发酵周期为192h以及发酵过程的pH应控制在6.4附近。连续上了三批发酵罐,结果表明在16L发酵罐上的博莱霉素发酵单位可达105.11μg/ml。
Bleomycins that have antineoplastic property are a group of multi-component glycopeptide antibiotics produced by Streptomyces Vertillus. The difference of the components lies in the difference of the amine in the end. Bleomycins are broad antineoplastic medicine with low toxicity, they have a good curative effect on malignant lymphoma, and cancers of cervix, galactophore, esophagus, as well as liver cancer, which has a high incidence but no effective way to cure. So it is very important to improve the bleomycins content in the fermentation fluid.We optimize the components of the medium and the condition of culture, observe the impact of adding time and concentration of precursors on the yield of bleomycin. The impact of Carbon,organic substances, inorganic nitrogen,phosphate, and CuSO_4 on the fermentation of bleomycin. The optimum medium is: glucose1%, maltose 3%,soluble starch3%, soy peptone 0.5%, bean powder 3%, corn plasm1%, bean oil 0.5%, NaCl 0.3%, K_2HPO_4 0.1 % , ZnSO_4 0.05% , CuSO_4 0.01% , NaNO_3 0.3%. With the optimized fermentation medium, the yield of bleomycin produced by Streptomyces verticillus U-43 can reach 41.23μg/ml under the condition of flask culture. On the process of optimizing culture condition , impact of the innoculation time, innoculation content, primary pH of fermentation medium, flask column on fermentation have been studied.the results show that the innoculation time is 48h, optimum temperature 28℃, most appropriate primary pH 6.0, innoculation content 6%, flask column 80ml/500ml. After optimization of culture condition, the output can reach 46.11μg/ml. Using the optimised fermentation medium and condition,and addition of the precursor refined amine 0.04 mg/ml when the fermentation comes to 60h..Based on the results in shake flasks, bleomycin fermentation was scaled up in a 16L fermentor.The metabolic characteristic of Streptomyces verticillus U-43 in the 16L fermentor ,including pH, sugar and nitrogen metablization,biomass,dissolved oxygen, productivity of per unit.it is established that the critical point of the dissolved oxygen should be no lower than 20%, the fermentation period is 192 hours,and pH should be controlled at about 6.4,the findings of three consecutive fermentation show that the fermentation unit of bleomycin can reach 105.11 μg /ml.
从博莱霉素的摇瓶发酵着手,对培养基组成和培养条件进行了优化,并考察了前体加入时间和加入浓度对博莱霉素产量的影响。考察了碳源、有机氮源、无机氮源、磷酸盐和CuSO_4对博莱霉素发酵的影响,确定了最佳发酵培养基配方为:葡萄糖1%,麦芽糖3%,可溶性淀粉3%,大豆蛋白胨0.5%,黄豆饼粉3%,玉米浆1%,豆油0.5%,NaCl 0.3%,K_2HPO_4 0.1%,ZnSO_4 0.05%,CHSO_4 0.01%,NaNO_3 0.3%,优化后的发酵培养基使链霉菌Streptomyces verticillus U-43在摇瓶培养条件下博来霉素的产量达到41.23μg/ml。在对链霉菌Streptomyces verticillus U-43的培养条件优化的过程中,分别考察了接种龄、接种量、发酵培养基初始pH值、摇瓶装液量对发酵的影响,结果表明:链霉菌Streptomyces verticillus U-43的最适接种龄为48h,最佳培养温度为28℃,发酵培养基的最适初始pH为6.0,接种量为6%,摇瓶装液量为80ml/500ml△。经发酵培养条件优化后,链霉菌Streptomyces verticillus U-43在摇瓶培养条件下博莱霉素的产量达到46.11μg/ml。采用优化的发酵培养基配方和发酵条件,并在发酵进行至60h添加0.04mg/ml的前体精胺,可明显提高效价,其摇瓶效价达62.21μg/ml。
以摇瓶发酵实验为基础,进行了博莱霉素发酵由摇瓶到16L发酵罐的放大,考察了轮枝链霉菌(Streptomyces verticillus)U-43在16L发酵罐中的代谢特性,包括发酵过程中的pH、糖代谢、氮代谢、生物量、溶氧、效价,确定了发酵的溶氧临界点不低于20%、发酵周期为192h以及发酵过程的pH应控制在6.4附近。连续上了三批发酵罐,结果表明在16L发酵罐上的博莱霉素发酵单位可达105.11μg/ml。
Bleomycins that have antineoplastic property are a group of multi-component glycopeptide antibiotics produced by Streptomyces Vertillus. The difference of the components lies in the difference of the amine in the end. Bleomycins are broad antineoplastic medicine with low toxicity, they have a good curative effect on malignant lymphoma, and cancers of cervix, galactophore, esophagus, as well as liver cancer, which has a high incidence but no effective way to cure. So it is very important to improve the bleomycins content in the fermentation fluid.We optimize the components of the medium and the condition of culture, observe the impact of adding time and concentration of precursors on the yield of bleomycin. The impact of Carbon,organic substances, inorganic nitrogen,phosphate, and CuSO_4 on the fermentation of bleomycin. The optimum medium is: glucose1%, maltose 3%,soluble starch3%, soy peptone 0.5%, bean powder 3%, corn plasm1%, bean oil 0.5%, NaCl 0.3%, K_2HPO_4 0.1 % , ZnSO_4 0.05% , CuSO_4 0.01% , NaNO_3 0.3%. With the optimized fermentation medium, the yield of bleomycin produced by Streptomyces verticillus U-43 can reach 41.23μg/ml under the condition of flask culture. On the process of optimizing culture condition , impact of the innoculation time, innoculation content, primary pH of fermentation medium, flask column on fermentation have been studied.the results show that the innoculation time is 48h, optimum temperature 28℃, most appropriate primary pH 6.0, innoculation content 6%, flask column 80ml/500ml. After optimization of culture condition, the output can reach 46.11μg/ml. Using the optimised fermentation medium and condition,and addition of the precursor refined amine 0.04 mg/ml when the fermentation comes to 60h..Based on the results in shake flasks, bleomycin fermentation was scaled up in a 16L fermentor.The metabolic characteristic of Streptomyces verticillus U-43 in the 16L fermentor ,including pH, sugar and nitrogen metablization,biomass,dissolved oxygen, productivity of per unit.it is established that the critical point of the dissolved oxygen should be no lower than 20%, the fermentation period is 192 hours,and pH should be controlled at about 6.4,the findings of three consecutive fermentation show that the fermentation unit of bleomycin can reach 105.11 μg /ml.
引文
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