基于多尺度参数相关分析的阿维菌素发酵过程优化及工业规模放大研究
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摘要
阿维菌素(Avermectin, AVM)是由阿维链霉菌(Streptomyces avermitilis)发酵产生的一类具有广泛杀虫和抗寄生虫等生物活性的抗生素,占我国生物农药50%以上,市场份额巨大。我国虽有众多厂家生产阿维菌素,但鉴于我国目前的阿维菌素发酵水平与国际相比还有很大差距,本论文以发酵过程多尺度参数相关的宏观代谢调控为手段,对阿维菌素工业生产菌种选育及发酵过程优化与放大策略进行了系统研究,具体结果如下：
1.阿维菌素高产菌株的推理选育及接种生理特性研究
以工业生产菌株AV-023为出发菌株,针对国内阿维菌素菌种发酵有效组分低,菌株对还原糖浓度敏感的特性,开展对该菌株进行提高阿维菌素有效组分Bla的推理选育和耐高还原糖浓度驯化研究。获得了高产突变菌株AV60s-32,阿维菌素Bla单位可达4520 IU/ml,比出发菌株提高了23.4%,同时,该突变菌株的耐高还原糖浓度能力从2%扩大到5%,为阿维菌素发酵补糖策略优化与放大奠定了重要基础。此外,孢子接种和挖块接种的发酵宏观代谢生理参数OUR具有显著的差别：孢子接种发酵前期OUR峰值较低(15～20 mmol/1/h),后期下降较慢,OUR较平稳(9～11 mmol/1/h),而挖块接种发酵过程OUR变化相反,最终孢子接种发酵效价比挖块接种效价(4493 IU/ml)高9.8%,这一现象为阿维菌素发酵前期调控和后期发酵补糖策略提供了有益思路。
2.阿维菌素发酵培养基优化及发酵前期OUR调控研究
阿维菌素工业生产菌株对营养需求极为复杂,孢子培养基中添加0.01%的Mg2+可促进菌株的孢子形成。采用中心组合试验设计(CCD)对棉籽饼粉替代酵母粉的发酵培养基进行优化,获得了全新的发酵培养基配方：玉米淀粉14.22%,棉籽饼粉1.19%,豆粕粉2.67%,硫酸铵0.05%,钼酸钠0.0023%,CoCl20.0023%,硫酸锰0.00023%。优化后阿维菌素发酵效价达到5235 IU/ml,比优化前(4450 IU/ml)提高了17.6%。同时,对2M3中试罐进行多尺度宏观代谢参数相关分析,发现发酵前期将OUR峰值控制在15～20 mmol/1/h,发酵后期菌体代谢能力较强,OUR变化较平稳,该控制策略能促进阿维菌素生物合成前体有机酸的积累,显著提高发酵后期阿维菌素的生物合成速率。
3.建立了基于OUR调控的阿维菌素补糖发酵新策略
通过对阿维菌素发酵过程补糖策略进行优化,发现以OUR为依据进行补糖,在发酵150h后,控制OUR在10～12 mmol/1/h,阿维菌素B1。效价为6430IU/ml,比对照(5250 IU/ml)提高了22.5%。对该策略的代谢机理进行初步分析表明,以OUR为依据的补糖策略促进了阿维菌素生物合成的直接前体物质丙酸、乙酸和支链氨基酸的积累。通过进一步对阿维菌素生物合成代谢途径关键酶活测定结果证实：柠檬酸合成酶活性明显提高,表明TCA循环的代谢通量得到加强；甲基丙二酰辅酶A变位酶活性极大的提高,表明导向阿维菌素生物合成的前体代谢通量增大,强化了阿维菌素合成的代谢流。
4.基于细胞生理特性与流场特性相结合的发酵过程放大研究
通过对阿维链霉菌菌形进行定量计算和发酵流体特性分析,建立了阿维菌素发酵液流体特性与菌形之间的数学模型。150 M3发酵罐流场计算流体力学(CFD)模拟表明,采用分批补糖策略时阿维菌素发酵罐中的气含率、剪切应力等参数有助于反应器流场特性的改善。通过CFD分析流场特性,采用多尺度参数相关分析与流场特性(CFD)研究相结合的方法,成功实现了基于OUR调控的阿维菌素补糖新策略在工业规模150 M3发酵罐上的放大,建立了以微生物细胞生理特性(菌形、OUR)与生物反应器流场特性相结合的阿维菌素发酵补糖策略的理性放大方法。进一步揭示了以OUR调控的阿维菌素发酵补糖策略成功放大到150M3工业规模的合理性,为微生物发酵过程优化与放大提供借鉴和参考依据。
Avermectins, a broad-spectrum and highly effective bio-pesticide, is a prominent member of the macrolide antibiotics produced by Streptomyces avermitilis. As an effective and low toxicity pesticidal antibiotic, avermectins exceeds 50% in the pesticide market in China. But avermectin B1a industry by fermentation biotechnology in China lags far behind international advanced level. Aimed at this situation, the fermentation process physiological characteristics, glucose feeding strategy and fluid dynamics of avermectin production by S. avermitilis as well as its industrial scale-up methodology were investigated based on multi scale parameter association analysis.
1. Rational breeding of high avermectin B1a yield industrial strain and its physiological characteristic study under different inoculum types
Strain Biok Av-023 used as the control was employed on screening of high-avermectin B1a-yield mutants by rational screening using He as screening pressure and resistance of high reducing sugar concentration. The result showed that the maximum avermectin B1a production of a mutant stain AV60s-32 reached 4520 IU/ml, which was 23.4% higher than the control. Also, mutant av60s-32 can withstand a higher reducing sugar concentration (increased from 2% to 5%). Oxygen uptake rate (OUR) during fermentation process was significantly different when two inoculation types were employed,i.e. spores inoculum and vegetative inoculum. Although lower OUR (15～20 mmol/1/h) occurred with spore inoculum during the early stage of fermentation, a stable OUR (9～11 mmol/1/h) was obtained in the late stage of fermentation, which corresponded to 9.8% greater avermectin B1a production than that obtained with vegetative inoculum (4493 IU/ml) in 2 M3 fermentor.
2. Optimization of nutritional requirements for avermectin producion and OUR control strategy in the early stage of fermentation process
Industrial strain requires very complex nutritent for avermectin production. Experiments showed that adding 0.01% Mg2+ in the slant medium increased spore formation and avermectin production of S. avermitilis. Using statistical methods (CCD) to optimize the fermentation medium, a new avermectin production medium was obtained as follows:corn starch 14.2%, cottonseed meal 1.2%, soya bean meal 2.7%. Avermectin B1a titer of 5235 IU/ml was obtained by the optimal medium in shake flask, which was 17.6% higher than the control. It was found that OUR was strongly influenced by cell growth and antibiotics production based on multi-parameters association analysis in fermentation process. Avermectin B1a biosynthesis could be effectively enhanced when OUR was stably regulated at an appropriate level in batch fermentation of S. avermitilis. Avermectin. B1a yield was improved by controlling maximal OUR between 15 mmol/l/h and 20 mmol/l/h during cell growth phase. This stimulation effect on avermectin B1a production could be attributed to the improved supply of propionic acid and acetic acid, the precursors of Avermectin B1a, in the cells. Hence, this OUR control method during cell growth phase should be applicable to avermectin industry.
3. A novel glucose feeding strategy for avermectin production based on OUR regulation.
The results showed that, avermectin B1a 6430 IU/ml was achieved based on OUR control feeding strategy, which was 22.5% higher than the control (5250 IU/ml), when controlling OUR in the range of 10-12 mmol/l/h during the fed-batch phase. OUR change was found to have close relationship with the trends of pH, organic acids, amino acids and some key enzyme activities of avermectin biosynthetic pathway. After 150 h of fermentation, the accumulation of intracellular pyruvate, propionic acid and acetic acid, which were precusor organic acids for avermectin biosynthesis, was significantly higher than that of the control. The analysis of the amino acids in the broth revealed that threonine and methionine achieved the maximum accumulation at 200 h, and alanine, valine, leucine and isoleucine were higher than that of the control. These data indicated that the precursor amino acids pool was abundant when OUR control was used to regulate the glucose feeding. Further study on the key enzyme activity in avermectin biosynthesis pathway showed that citrate synthase activity was significantly increased, suggesting that the TCA metabolic flux was increased, which was consistent to the results of organic acid analysis. Methyl malonyl coenzyme A activity greatly increased at 200 h, indicating that the node of the precursors for avermectin biosynthesis was strengthened. It was beneficial to the high rate of precursor supply for avermectin biosynthesis using the OUR feeding strategy.
4. Scale up of avermectin B1a production by integrating fluid dynamics and cell physiology.
A relationship between the broth fluid properties and the mycelial morphology was established through morphology quantitative calculation and fluid dynamics analysis. In addition, computational fluid dynamics (CFD) was employed for the analysis of fluid dynamics in 150 m3 fermentor. It was found that fluid characteristics of avermectin production on industrial scale was improved when novel glucose feeding strategy was adopted by analyzing gas holdup, shear stress, mixing intensity, turbulent character in the bioreactor using CFD simulation. Based on flow dynamic analysis using CFD and cell physiology study of avermectin B1a production, the novel glucose feeding strategy by OUR regulation was successfully scaled up in a 150 m3 fermenter, which would provide a scientific basis for other microbial fermentation process optimization and scale up.
1.阿维菌素高产菌株的推理选育及接种生理特性研究
以工业生产菌株AV-023为出发菌株,针对国内阿维菌素菌种发酵有效组分低,菌株对还原糖浓度敏感的特性,开展对该菌株进行提高阿维菌素有效组分Bla的推理选育和耐高还原糖浓度驯化研究。获得了高产突变菌株AV60s-32,阿维菌素Bla单位可达4520 IU/ml,比出发菌株提高了23.4%,同时,该突变菌株的耐高还原糖浓度能力从2%扩大到5%,为阿维菌素发酵补糖策略优化与放大奠定了重要基础。此外,孢子接种和挖块接种的发酵宏观代谢生理参数OUR具有显著的差别：孢子接种发酵前期OUR峰值较低(15～20 mmol/1/h),后期下降较慢,OUR较平稳(9～11 mmol/1/h),而挖块接种发酵过程OUR变化相反,最终孢子接种发酵效价比挖块接种效价(4493 IU/ml)高9.8%,这一现象为阿维菌素发酵前期调控和后期发酵补糖策略提供了有益思路。
2.阿维菌素发酵培养基优化及发酵前期OUR调控研究
阿维菌素工业生产菌株对营养需求极为复杂,孢子培养基中添加0.01%的Mg2+可促进菌株的孢子形成。采用中心组合试验设计(CCD)对棉籽饼粉替代酵母粉的发酵培养基进行优化,获得了全新的发酵培养基配方：玉米淀粉14.22%,棉籽饼粉1.19%,豆粕粉2.67%,硫酸铵0.05%,钼酸钠0.0023%,CoCl20.0023%,硫酸锰0.00023%。优化后阿维菌素发酵效价达到5235 IU/ml,比优化前(4450 IU/ml)提高了17.6%。同时,对2M3中试罐进行多尺度宏观代谢参数相关分析,发现发酵前期将OUR峰值控制在15～20 mmol/1/h,发酵后期菌体代谢能力较强,OUR变化较平稳,该控制策略能促进阿维菌素生物合成前体有机酸的积累,显著提高发酵后期阿维菌素的生物合成速率。
3.建立了基于OUR调控的阿维菌素补糖发酵新策略
通过对阿维菌素发酵过程补糖策略进行优化,发现以OUR为依据进行补糖,在发酵150h后,控制OUR在10～12 mmol/1/h,阿维菌素B1。效价为6430IU/ml,比对照(5250 IU/ml)提高了22.5%。对该策略的代谢机理进行初步分析表明,以OUR为依据的补糖策略促进了阿维菌素生物合成的直接前体物质丙酸、乙酸和支链氨基酸的积累。通过进一步对阿维菌素生物合成代谢途径关键酶活测定结果证实：柠檬酸合成酶活性明显提高,表明TCA循环的代谢通量得到加强；甲基丙二酰辅酶A变位酶活性极大的提高,表明导向阿维菌素生物合成的前体代谢通量增大,强化了阿维菌素合成的代谢流。
4.基于细胞生理特性与流场特性相结合的发酵过程放大研究
通过对阿维链霉菌菌形进行定量计算和发酵流体特性分析,建立了阿维菌素发酵液流体特性与菌形之间的数学模型。150 M3发酵罐流场计算流体力学(CFD)模拟表明,采用分批补糖策略时阿维菌素发酵罐中的气含率、剪切应力等参数有助于反应器流场特性的改善。通过CFD分析流场特性,采用多尺度参数相关分析与流场特性(CFD)研究相结合的方法,成功实现了基于OUR调控的阿维菌素补糖新策略在工业规模150 M3发酵罐上的放大,建立了以微生物细胞生理特性(菌形、OUR)与生物反应器流场特性相结合的阿维菌素发酵补糖策略的理性放大方法。进一步揭示了以OUR调控的阿维菌素发酵补糖策略成功放大到150M3工业规模的合理性,为微生物发酵过程优化与放大提供借鉴和参考依据。
Avermectins, a broad-spectrum and highly effective bio-pesticide, is a prominent member of the macrolide antibiotics produced by Streptomyces avermitilis. As an effective and low toxicity pesticidal antibiotic, avermectins exceeds 50% in the pesticide market in China. But avermectin B1a industry by fermentation biotechnology in China lags far behind international advanced level. Aimed at this situation, the fermentation process physiological characteristics, glucose feeding strategy and fluid dynamics of avermectin production by S. avermitilis as well as its industrial scale-up methodology were investigated based on multi scale parameter association analysis.
1. Rational breeding of high avermectin B1a yield industrial strain and its physiological characteristic study under different inoculum types
Strain Biok Av-023 used as the control was employed on screening of high-avermectin B1a-yield mutants by rational screening using He as screening pressure and resistance of high reducing sugar concentration. The result showed that the maximum avermectin B1a production of a mutant stain AV60s-32 reached 4520 IU/ml, which was 23.4% higher than the control. Also, mutant av60s-32 can withstand a higher reducing sugar concentration (increased from 2% to 5%). Oxygen uptake rate (OUR) during fermentation process was significantly different when two inoculation types were employed,i.e. spores inoculum and vegetative inoculum. Although lower OUR (15～20 mmol/1/h) occurred with spore inoculum during the early stage of fermentation, a stable OUR (9～11 mmol/1/h) was obtained in the late stage of fermentation, which corresponded to 9.8% greater avermectin B1a production than that obtained with vegetative inoculum (4493 IU/ml) in 2 M3 fermentor.
2. Optimization of nutritional requirements for avermectin producion and OUR control strategy in the early stage of fermentation process
Industrial strain requires very complex nutritent for avermectin production. Experiments showed that adding 0.01% Mg2+ in the slant medium increased spore formation and avermectin production of S. avermitilis. Using statistical methods (CCD) to optimize the fermentation medium, a new avermectin production medium was obtained as follows:corn starch 14.2%, cottonseed meal 1.2%, soya bean meal 2.7%. Avermectin B1a titer of 5235 IU/ml was obtained by the optimal medium in shake flask, which was 17.6% higher than the control. It was found that OUR was strongly influenced by cell growth and antibiotics production based on multi-parameters association analysis in fermentation process. Avermectin B1a biosynthesis could be effectively enhanced when OUR was stably regulated at an appropriate level in batch fermentation of S. avermitilis. Avermectin. B1a yield was improved by controlling maximal OUR between 15 mmol/l/h and 20 mmol/l/h during cell growth phase. This stimulation effect on avermectin B1a production could be attributed to the improved supply of propionic acid and acetic acid, the precursors of Avermectin B1a, in the cells. Hence, this OUR control method during cell growth phase should be applicable to avermectin industry.
3. A novel glucose feeding strategy for avermectin production based on OUR regulation.
The results showed that, avermectin B1a 6430 IU/ml was achieved based on OUR control feeding strategy, which was 22.5% higher than the control (5250 IU/ml), when controlling OUR in the range of 10-12 mmol/l/h during the fed-batch phase. OUR change was found to have close relationship with the trends of pH, organic acids, amino acids and some key enzyme activities of avermectin biosynthetic pathway. After 150 h of fermentation, the accumulation of intracellular pyruvate, propionic acid and acetic acid, which were precusor organic acids for avermectin biosynthesis, was significantly higher than that of the control. The analysis of the amino acids in the broth revealed that threonine and methionine achieved the maximum accumulation at 200 h, and alanine, valine, leucine and isoleucine were higher than that of the control. These data indicated that the precursor amino acids pool was abundant when OUR control was used to regulate the glucose feeding. Further study on the key enzyme activity in avermectin biosynthesis pathway showed that citrate synthase activity was significantly increased, suggesting that the TCA metabolic flux was increased, which was consistent to the results of organic acid analysis. Methyl malonyl coenzyme A activity greatly increased at 200 h, indicating that the node of the precursors for avermectin biosynthesis was strengthened. It was beneficial to the high rate of precursor supply for avermectin biosynthesis using the OUR feeding strategy.
4. Scale up of avermectin B1a production by integrating fluid dynamics and cell physiology.
A relationship between the broth fluid properties and the mycelial morphology was established through morphology quantitative calculation and fluid dynamics analysis. In addition, computational fluid dynamics (CFD) was employed for the analysis of fluid dynamics in 150 m3 fermentor. It was found that fluid characteristics of avermectin production on industrial scale was improved when novel glucose feeding strategy was adopted by analyzing gas holdup, shear stress, mixing intensity, turbulent character in the bioreactor using CFD simulation. Based on flow dynamic analysis using CFD and cell physiology study of avermectin B1a production, the novel glucose feeding strategy by OUR regulation was successfully scaled up in a 150 m3 fermenter, which would provide a scientific basis for other microbial fermentation process optimization and scale up.
引文
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