产普那霉素始旋链霉菌发酵的代谢调控、条件优化及软测量建模研究
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摘要
普那霉素是由始旋链霉菌产生的链阳性菌素类抗生素,由普那霉素Ⅰ和普那霉素Ⅱ两类化合物组成,对包括耐药菌在内的大多数革兰氏阳性菌均具有较强的杀菌活性,且抗生素后效应较长,因此被公认为是治疗顽固性革兰氏阳性菌感染的首选药物。本文以提高普那霉素发酵产量及其优化控制为目标,对培养基组分在普那霉素生物合成的调控机理、溶氧及合成前体对其生物合成的影响开展了较系统的研究,并探索利用支持向量机模型建立发酵过程重要参数的预测模型。主要结果摘要如下：
培养基关键组分对普那霉素生物合成的调控机理分析首先就培养基中葡萄糖、铵离子及磷酸盐等组分对普那霉素生物合成的调控机理进行研究,发现高浓度的葡萄糖、磷酸盐及铵离子可抑制普那霉素的合成。当葡萄糖浓度、磷酸盐和铵离子浓度分别高于30g/L、1.5mM及15mM时,普那霉素的合成量大大降低。进一步研究显示,葡萄糖和磷酸盐主要通过糖的磷酸化以及葡萄糖-6-磷酸的积累反馈而抑制糖分解代谢,从而抑制普那霉素的生物合成；而铵离子则通过抑制糖酵解(EMP)途径和己糖一磷酸途径(HMP),激活三羧酸循环关键酶,起到对普那霉素生物合成的调控作用。
添加氧载体对普那霉素生物合成的影响考察了在摇瓶中添加氧载体或乳化氧载体对普那霉素发酵的影响。加入适量氧载体或乳化氧载体有利于改善发酵液中的氧传递,使得菌丝体生长良好,普那霉素产量明显高于对照组。在发酵36h时添加10%经0.01%二甲基硅油乳化的正十六烷,普那霉素的产量达到180.6mg/L,为对照组产量的3.1倍。同时考察了菌丝体形态和普那霉素生物合成的关系,添加乳化氧载体后,菌丝团较疏松,有利于氧和营养物质的传递,似为普那霉素产量提高的主要原因。
基于普那霉素生物合成途径的发酵条件优化以已知的生物合成途径为切入点,研究进一步提高普那霉素产量的发酵优化策略。结果表明,在发酵培养基中加入0.2%的正丙醇,普那霉素产量比对照提高135.2%。此外,评价了氨基酸前体对普那霉素发酵的影响,由此建立了以甘氨酸作为最佳前体在摇瓶发酵的优化添加策略。继之,利用3L发酵罐进行了耦合树脂原位吸附分离的扩大发酵试验,在发酵36h时添加0.75g/L甘氨酸,并在20h时添加树脂进行原位分离,此时普那霉素的最高产量可达到616mg/L,分别为仅添加甘氨酸、树脂及对照处理的1.7、2.8及4.3倍,这一结果表明,添加甘氨酸耦合树脂的原位吸附分离是提高始旋链霉菌F213发酵生产普那霉素产量的有效途径。
基于支持向量机的发酵过程软测量建模生物发酵过程通常具有机理复杂性、高度非线性及生物参数难以在线实时测量的特点,在成功利用支持向量机理论建立植物乳杆菌的菌体浓度v-SVR软测量模型的基础上,对普那霉素发酵产量及菌体浓度建立了v-SVR预测模型,结果表明,利用支持向量机理论建立的产物浓度及菌体浓度软测量模型拟合误差小,推广性能好,可作为发酵过程优化控制的参考依据。
Pristinamycin is an antibiotic of the streptogramin family produced by Streptomyces pristinaespiralis and consists of two components, i.e., pristinamycin Ⅰ (PⅠ) and pristinamycin Ⅱ (PⅡ). Due to its strong, prolonged activity against most gram-positive bacteria including drug-resistant pathogens, pristinamycin is considered as a preferred antibiotic to fight against stubborn gram-positive bacterial infections. To increase the production of pristinamycin during fermentation, this study sought to ellucidate the effects of medium components on the biosynthesis of pristinamycin with an emphasis placed upon the screening of appropriate oxygen vectors and fatty acid or amino acid precursors for inclusion, and to establish an optimized strategy that enables to enhance pristinamycin yield by feeding pristinamycin precursor. The results are summarized below.
Effects of key medium components on pristinamycin biosynthesis. The effects of glucose, ammonium ions and phosphate on pristinamycin biosynthesis during the submerged culture of Streptomyces pristinaespiralis F213in flasks were assesed. Pristinamycin biosynthesis was suppressed by high concentration of glucose, ammonium ions, and phosphate in basal fermentation medium. The concentrations of glucose, phosphate, and ammonium ions exceeding30g/L,1.5mM and15mM in the basal medium respectively resulted in decreased pristinamycin yields. The high glucose and phosphate concentrations were found to increase glucose-6-phosphate accumulation for the suppression of glucose catabolism and thus pristinamycin biosynthesis, while concentrated NH4+could inactivate some enzymes involved in Embden-Meyerhof-Parnas (EMP) pathway and Hexose Monophophate pathway (HMP) but activate enzymes involved in tricarboxylic acid (TCA) cycle.
Effects of oxygen vectors on pristinamycin biosynthesis. Cyclohexane, N-heptane, N-hexane and hexadecane as added oxygen vectors were compared with blank control for their effects on pristinamycin biosynthesis in flask cultures. Of those, hexadecane was the best oxygen vector to improve oxygen transfer, resulting in a pristinamycin yield97.4%higher than control. After10%(w/v) emulsified hexadecane (with0.01%dimethyl silicone) was added to the culture at the time of36h fermentation, a maximal pristinamycin yield of180.6mg/L was achieved after the fermentation continued for36h. This yield was3.1fold of the control counterpart. In addition, the emulsified hexadecane was superior to its un-emulsified form in the improvement of oxygen and nutrient transfer, thus favoring the biosynthesis of pristinamycin.
Fermentation optimization based on the biosynthesis pathway of pristinamycin. Based on the known biosynthesis pathway and the metabolic regulation of pristinamycin, the fermentation strategy was further optimized to increase the yield of pristinamycin in flasks and3L bioreactor. Five fatty acids (or alcohol) and seven aminoacids were compared as pristinamycin precursors for their effects on pristinamycin biosynthesis. Of those,0.2%propanol added to the fermentation medium resulted in135.2%increase in pristinamycin yield while inclusion of1g/L glycine in the medium enhanced the yield by1.9fold compared with the control yield. The feeding concentration and time of glycine was furher optimized as0.75g/L at the time of36h fermentation. This optimized glycine feeding strategy was applied to enlarged3L bioreactor fermentation with8%resin added at the time of20h fermentation for in situ separation. The combination of resin and glycine feeding resulted in the maximal pristinamycin yield of616mg/L at the time of12h after glycine feeding. This yield was1.71,2.77and4.32fold of those from the mere glycine and resin treatments and the control, respectively. The results indicated that glycine feeding is an effective approach to enhancing pristinamycin production in the culture of S. pristinaespiralis F213with supplemented resin for in situ separation.
Soft sensor modeling in fermentation process based on support vector machine. Support vector machine (S VM) theory was adopted to establish S VM model for fitting the mycelium biomass and pristinamycin yield measurements of S. pristinaespiralis F213from the3L bioreactor. The model provided better fitness to the pristinamycin yield (R2=0.987) than the biomass (R2=0.863).
培养基关键组分对普那霉素生物合成的调控机理分析首先就培养基中葡萄糖、铵离子及磷酸盐等组分对普那霉素生物合成的调控机理进行研究,发现高浓度的葡萄糖、磷酸盐及铵离子可抑制普那霉素的合成。当葡萄糖浓度、磷酸盐和铵离子浓度分别高于30g/L、1.5mM及15mM时,普那霉素的合成量大大降低。进一步研究显示,葡萄糖和磷酸盐主要通过糖的磷酸化以及葡萄糖-6-磷酸的积累反馈而抑制糖分解代谢,从而抑制普那霉素的生物合成；而铵离子则通过抑制糖酵解(EMP)途径和己糖一磷酸途径(HMP),激活三羧酸循环关键酶,起到对普那霉素生物合成的调控作用。
添加氧载体对普那霉素生物合成的影响考察了在摇瓶中添加氧载体或乳化氧载体对普那霉素发酵的影响。加入适量氧载体或乳化氧载体有利于改善发酵液中的氧传递,使得菌丝体生长良好,普那霉素产量明显高于对照组。在发酵36h时添加10%经0.01%二甲基硅油乳化的正十六烷,普那霉素的产量达到180.6mg/L,为对照组产量的3.1倍。同时考察了菌丝体形态和普那霉素生物合成的关系,添加乳化氧载体后,菌丝团较疏松,有利于氧和营养物质的传递,似为普那霉素产量提高的主要原因。
基于普那霉素生物合成途径的发酵条件优化以已知的生物合成途径为切入点,研究进一步提高普那霉素产量的发酵优化策略。结果表明,在发酵培养基中加入0.2%的正丙醇,普那霉素产量比对照提高135.2%。此外,评价了氨基酸前体对普那霉素发酵的影响,由此建立了以甘氨酸作为最佳前体在摇瓶发酵的优化添加策略。继之,利用3L发酵罐进行了耦合树脂原位吸附分离的扩大发酵试验,在发酵36h时添加0.75g/L甘氨酸,并在20h时添加树脂进行原位分离,此时普那霉素的最高产量可达到616mg/L,分别为仅添加甘氨酸、树脂及对照处理的1.7、2.8及4.3倍,这一结果表明,添加甘氨酸耦合树脂的原位吸附分离是提高始旋链霉菌F213发酵生产普那霉素产量的有效途径。
基于支持向量机的发酵过程软测量建模生物发酵过程通常具有机理复杂性、高度非线性及生物参数难以在线实时测量的特点,在成功利用支持向量机理论建立植物乳杆菌的菌体浓度v-SVR软测量模型的基础上,对普那霉素发酵产量及菌体浓度建立了v-SVR预测模型,结果表明,利用支持向量机理论建立的产物浓度及菌体浓度软测量模型拟合误差小,推广性能好,可作为发酵过程优化控制的参考依据。
Pristinamycin is an antibiotic of the streptogramin family produced by Streptomyces pristinaespiralis and consists of two components, i.e., pristinamycin Ⅰ (PⅠ) and pristinamycin Ⅱ (PⅡ). Due to its strong, prolonged activity against most gram-positive bacteria including drug-resistant pathogens, pristinamycin is considered as a preferred antibiotic to fight against stubborn gram-positive bacterial infections. To increase the production of pristinamycin during fermentation, this study sought to ellucidate the effects of medium components on the biosynthesis of pristinamycin with an emphasis placed upon the screening of appropriate oxygen vectors and fatty acid or amino acid precursors for inclusion, and to establish an optimized strategy that enables to enhance pristinamycin yield by feeding pristinamycin precursor. The results are summarized below.
Effects of key medium components on pristinamycin biosynthesis. The effects of glucose, ammonium ions and phosphate on pristinamycin biosynthesis during the submerged culture of Streptomyces pristinaespiralis F213in flasks were assesed. Pristinamycin biosynthesis was suppressed by high concentration of glucose, ammonium ions, and phosphate in basal fermentation medium. The concentrations of glucose, phosphate, and ammonium ions exceeding30g/L,1.5mM and15mM in the basal medium respectively resulted in decreased pristinamycin yields. The high glucose and phosphate concentrations were found to increase glucose-6-phosphate accumulation for the suppression of glucose catabolism and thus pristinamycin biosynthesis, while concentrated NH4+could inactivate some enzymes involved in Embden-Meyerhof-Parnas (EMP) pathway and Hexose Monophophate pathway (HMP) but activate enzymes involved in tricarboxylic acid (TCA) cycle.
Effects of oxygen vectors on pristinamycin biosynthesis. Cyclohexane, N-heptane, N-hexane and hexadecane as added oxygen vectors were compared with blank control for their effects on pristinamycin biosynthesis in flask cultures. Of those, hexadecane was the best oxygen vector to improve oxygen transfer, resulting in a pristinamycin yield97.4%higher than control. After10%(w/v) emulsified hexadecane (with0.01%dimethyl silicone) was added to the culture at the time of36h fermentation, a maximal pristinamycin yield of180.6mg/L was achieved after the fermentation continued for36h. This yield was3.1fold of the control counterpart. In addition, the emulsified hexadecane was superior to its un-emulsified form in the improvement of oxygen and nutrient transfer, thus favoring the biosynthesis of pristinamycin.
Fermentation optimization based on the biosynthesis pathway of pristinamycin. Based on the known biosynthesis pathway and the metabolic regulation of pristinamycin, the fermentation strategy was further optimized to increase the yield of pristinamycin in flasks and3L bioreactor. Five fatty acids (or alcohol) and seven aminoacids were compared as pristinamycin precursors for their effects on pristinamycin biosynthesis. Of those,0.2%propanol added to the fermentation medium resulted in135.2%increase in pristinamycin yield while inclusion of1g/L glycine in the medium enhanced the yield by1.9fold compared with the control yield. The feeding concentration and time of glycine was furher optimized as0.75g/L at the time of36h fermentation. This optimized glycine feeding strategy was applied to enlarged3L bioreactor fermentation with8%resin added at the time of20h fermentation for in situ separation. The combination of resin and glycine feeding resulted in the maximal pristinamycin yield of616mg/L at the time of12h after glycine feeding. This yield was1.71,2.77and4.32fold of those from the mere glycine and resin treatments and the control, respectively. The results indicated that glycine feeding is an effective approach to enhancing pristinamycin production in the culture of S. pristinaespiralis F213with supplemented resin for in situ separation.
Soft sensor modeling in fermentation process based on support vector machine. Support vector machine (S VM) theory was adopted to establish S VM model for fitting the mycelium biomass and pristinamycin yield measurements of S. pristinaespiralis F213from the3L bioreactor. The model provided better fitness to the pristinamycin yield (R2=0.987) than the biomass (R2=0.863).
引文
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