Burkholderia thailandensis E264生产抗癌药物Thailandepsin A的研究
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摘要
稀有的伯克氏菌E264(Burkholderia thailandensis E264)是从泰国稻田中分离得到的,能够合成具有双环缩肽结构的物质Thailandepsin A。Thailandepins A是一类组蛋白去乙酰化酶抑制剂(HDACI),是抗癌药物FK228的结构类似物,对多种耐药性肿瘤具显著作用。目前,野生型菌株合成Thailandepsin A产量很低(10mg/L),不适合进行大规模商业化应用,本论文试图通过培养基优化和大孔树脂原位富集的方法来提高Thailandepins A的产量。
首先,通过单因子实验对伯克氏菌E264的发酵条件和培养基成分进行初筛,确定了碳源、氮源、无机盐的种类,以及温度、pH值、摇床转速等因素的最佳条件。在温度28°C,250ml的摇瓶,装液量为65 ml,接种量为1%,培养基pH值7.0的条件下,对培养基配方进行优化。其次,通过在伯克氏菌E264发酵培养基中添加大孔树脂HP-20对产物进行原位富集,可使大部分Thailadepsin A在培养的同时就被树脂吸附,从而降低了产物抑制,并简化了后续提取分离步骤,产物的总收率比对照(不添加树脂)提高了80%左右。大孔树脂的添加量为4 %,添加时间为发酵开始后12小时。以氯仿作为树脂的解析液时,产物的回收效果较好。
同时,运用部分因子设计确定主要因素的效应以及因素之间的相互作用,通过基于响应面法的中心组合设计构建模型,预测出最优的培养基配方(g/L):葡萄糖17.89,胰蛋白胨34.98,K2HPO4 20.44,KH2PO4 4.4,柠檬酸钠0.01。产量的实测值为236.7mg/L,与模型的预测值251.9mg/L相符合,证明了模型的正确性以及该优化后的培养基的效用。响应面法优化后的产量236.7mg/L比单因子优化后产量提高了2倍多。另外,对Thailandepsin A分批发酵动力学模型进行了研究,以Logistic和Luedeking-Piret方程为基础,建立了动力学模型,较好的描述了生物量(X),产物浓度(P)与底物浓度(S)的变化规律。该模型适用于初始糖浓度为15g/L左右时的分批发酵过程。
最后,在有效体积为3L的发酵罐中进行了伯克氏菌E264扩大培养初步探索。通过在发酵过程中添加HP-20大孔树脂,产量较空白对照提高了29%,为后续研究打下基础。
Rare Burkholderia thailandensis E264 was isolated from the rice field of Thailand. It can produce Thailandepsin A which contains a bicyclic peptide structure. Thailandepins A is a class of histone deacetylase inhibitors (HDACI) and a structural analogue of anti-cancer drugs FK228 with significant role in T-cell lymphoma and skin cancer therapy. Currently,Thailandepsin A yield produced by wild-type strain is very low (10mg / L) and is not suitable for large scale commercial applications. This paper attempts to employ fermentaition medium optimization and macroporous resin HP-20 situ extraction methods to improve Thailandepins A production.
In this study,We primarily screened out the proper age of seed, liquid volume (ml), inoculum (%), temperature, pH and rotary speed using one-factor-at-a-time screening. The medium components, including glucose, tryptone, phosphate and sodium citrate had significant effects on Thailandespin A production.
It is effective to change Thailandepsin A distribution in the fermentation broth by adding HP-20 resin in broth.The in situ extraction effect of macroporous resins on Thailandespin A decreased the negative feedback inhibition and provided a simpler separation step . The results showed that through addition of maeroporous resin HP-20 , the yield of Thailandepsin A was significantly increased by 80%.It gave a preferable yield when additive amount of resin is 4%(w/v),addtime is 12h and extract liquor is chloroform.
Statistics based experimental designs were applied to optimize the culture medium components for enhancing Thailandepsin A production by Burkholderia thailandensis E264. Based on a 24-1 fractional factorial design and a central composite design, an optimum concentration of glucose 17.89 g/L, typtone 34.98 g/L, K2HPO4 20.44 g/L, KH2PO4 4.4g/L and sodium citrate 0.01 g/L was obtained by response surface analysis. The predicted maximum Thailandepsin A yield was as high as 251.9 mg/L, and was further verified by validation experiments. 236.7mg/L Thailandespin A, was almost 2 fold compared to 104mg/L Thailandepsin A from one factor at a time optimization.
Thailandespin A fermentation kinetics was also investigated. Kinetic models based on the modified Logistic and Luedeking-Piret equations were developed, providing a good description of temporal variations of biomass(X), product (P) and substrate(S) in Thailandepsin A fermentation.These models were applicable in batch fermentations with initial glucose concentration at about 15g/L.
In a laboratory scale stirred tank bioreactor with a working volume of 3 L, the Thailandepsin A fermentation was studied to investigate the effect of macroporous resin in fermentor.In fermentation process, production of Thailandepsin A in the bioreactor added HP-20 resin was increased over 29% than the blank control.
首先,通过单因子实验对伯克氏菌E264的发酵条件和培养基成分进行初筛,确定了碳源、氮源、无机盐的种类,以及温度、pH值、摇床转速等因素的最佳条件。在温度28°C,250ml的摇瓶,装液量为65 ml,接种量为1%,培养基pH值7.0的条件下,对培养基配方进行优化。其次,通过在伯克氏菌E264发酵培养基中添加大孔树脂HP-20对产物进行原位富集,可使大部分Thailadepsin A在培养的同时就被树脂吸附,从而降低了产物抑制,并简化了后续提取分离步骤,产物的总收率比对照(不添加树脂)提高了80%左右。大孔树脂的添加量为4 %,添加时间为发酵开始后12小时。以氯仿作为树脂的解析液时,产物的回收效果较好。
同时,运用部分因子设计确定主要因素的效应以及因素之间的相互作用,通过基于响应面法的中心组合设计构建模型,预测出最优的培养基配方(g/L):葡萄糖17.89,胰蛋白胨34.98,K2HPO4 20.44,KH2PO4 4.4,柠檬酸钠0.01。产量的实测值为236.7mg/L,与模型的预测值251.9mg/L相符合,证明了模型的正确性以及该优化后的培养基的效用。响应面法优化后的产量236.7mg/L比单因子优化后产量提高了2倍多。另外,对Thailandepsin A分批发酵动力学模型进行了研究,以Logistic和Luedeking-Piret方程为基础,建立了动力学模型,较好的描述了生物量(X),产物浓度(P)与底物浓度(S)的变化规律。该模型适用于初始糖浓度为15g/L左右时的分批发酵过程。
最后,在有效体积为3L的发酵罐中进行了伯克氏菌E264扩大培养初步探索。通过在发酵过程中添加HP-20大孔树脂,产量较空白对照提高了29%,为后续研究打下基础。
Rare Burkholderia thailandensis E264 was isolated from the rice field of Thailand. It can produce Thailandepsin A which contains a bicyclic peptide structure. Thailandepins A is a class of histone deacetylase inhibitors (HDACI) and a structural analogue of anti-cancer drugs FK228 with significant role in T-cell lymphoma and skin cancer therapy. Currently,Thailandepsin A yield produced by wild-type strain is very low (10mg / L) and is not suitable for large scale commercial applications. This paper attempts to employ fermentaition medium optimization and macroporous resin HP-20 situ extraction methods to improve Thailandepins A production.
In this study,We primarily screened out the proper age of seed, liquid volume (ml), inoculum (%), temperature, pH and rotary speed using one-factor-at-a-time screening. The medium components, including glucose, tryptone, phosphate and sodium citrate had significant effects on Thailandespin A production.
It is effective to change Thailandepsin A distribution in the fermentation broth by adding HP-20 resin in broth.The in situ extraction effect of macroporous resins on Thailandespin A decreased the negative feedback inhibition and provided a simpler separation step . The results showed that through addition of maeroporous resin HP-20 , the yield of Thailandepsin A was significantly increased by 80%.It gave a preferable yield when additive amount of resin is 4%(w/v),addtime is 12h and extract liquor is chloroform.
Statistics based experimental designs were applied to optimize the culture medium components for enhancing Thailandepsin A production by Burkholderia thailandensis E264. Based on a 24-1 fractional factorial design and a central composite design, an optimum concentration of glucose 17.89 g/L, typtone 34.98 g/L, K2HPO4 20.44 g/L, KH2PO4 4.4g/L and sodium citrate 0.01 g/L was obtained by response surface analysis. The predicted maximum Thailandepsin A yield was as high as 251.9 mg/L, and was further verified by validation experiments. 236.7mg/L Thailandespin A, was almost 2 fold compared to 104mg/L Thailandepsin A from one factor at a time optimization.
Thailandespin A fermentation kinetics was also investigated. Kinetic models based on the modified Logistic and Luedeking-Piret equations were developed, providing a good description of temporal variations of biomass(X), product (P) and substrate(S) in Thailandepsin A fermentation.These models were applicable in batch fermentations with initial glucose concentration at about 15g/L.
In a laboratory scale stirred tank bioreactor with a working volume of 3 L, the Thailandepsin A fermentation was studied to investigate the effect of macroporous resin in fermentor.In fermentation process, production of Thailandepsin A in the bioreactor added HP-20 resin was increased over 29% than the blank control.
引文
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