基于多尺度创新原理的工业微生物高通量筛选平台构建及应用研究
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摘要
菌种是发酵技术的源头,菌种发酵水平是决定企业产品能否参与市场竞争的技术保证,因此,微生物高通量筛选技术的研究和应用是提升工业发酵技术的必由之路。本论文通过流体动力学模拟深孔板与普通摇瓶的液体流动速度与剪切力分布,研究微型化培养过程中的氧传递、物料混合等科学问题,解决高耗氧微生物的微型化培养的关键技术。论文先以高耗氧丝状真菌顶头孢霉为研究对象,构建了灵活通用型菌株高通量筛选模型,再以好氧菌红色糖多孢菌和红曲霉为高通量分析及微型化培养对象,验证了高通量筛选平台的准确与可行性,进一步推广了高通量筛选技术的应用。
首先以顶头孢霉为研究对象,建立了提高筛选效率防止漏筛的高通量菌种筛选方法。即将所有诱变后孢子悬液等分至深孔板,同时培养与检测,先筛选出具有高产特性的存在于孔板中某一深孔中的混合菌群,再进一步从中分离纯化获得高产菌株。所构建的高通量筛选方法提供给诱变株平等的筛选机会,有效克服了传统筛选的漏筛问题。将此高通量筛选方法成功应用于头孢菌素C (CPC)高产菌株筛选,成功获得了一株顶头孢霉高产菌株W-6,在50L发酵罐上CPC产量比出发菌株1-D1提高了近2倍。接着开展了基于多尺度创新原理的菌种筛选后技术的系统研究,分别从代谢特性、菌形变化规律、酶学分析、与CPC合成相关的重要基因转录水平及定量代谢流分析等角度对获得的高产菌株与出发菌株进行了系统分析比较,初步揭示了高产菌株的高产机理。其中,酶学水平上,比较了两菌株在初级代谢过程中的四种关键酶酶活,分别是葡萄糖-6-磷酸脱氢酶、柠檬酸合成酶、异柠檬酸裂解酶和苹果酸合成酶。结果表明高产菌株的异柠檬酸裂解酶和苹果酸合成酶活性明显提高,因此在补加豆油的情况下,乙醛酸循环途径活性的明显提高是导致CPC产量提高的重要原因。我们还对CPC合成途径中的关键酶ACV合成酶、扩环酶/羟化酶、酰基转移酶的编码基因pcbAB, cefEF和cefG进行了转录水平的比较。高产菌株W-6的pcbAB、cefEF、cefG在72h的mRNA转录水平分别是出发菌株(1-D1)的5、8、1.2倍；在96h分别是1-D1的5、14、1.5倍；在120h分别是1-D1的4、50、7倍。说明进入CPC合成期后cefEF转录差异最大,扩环酶/羟化酶的限制很可能是影响CPC合成增加的重要原因,从而为进一步基因改造或优化培养条件提供了有益线索。代谢流计算结果表明,顶头孢霉菌丝体内的碳主要是在以柠檬酸循环、乙醛酸循环和回补途径进行代谢,高产菌株消耗的豆油总量较多,经过代谢分解成的C2底物浓度较高,导致其TCA循环通量较大。高产菌株W-6进入乙醛酸循环途径中的C2底物的通量是出发菌株的1.43倍,能够生成更多的草酰乙酸进入到回补途径当中去,供给CPC合成所需要的NADPH以及前体氨基酸。
其次,以红曲霉生产菌红色糖多孢菌为研究对象建立了每次检测通量可达数千的高通量生物分析法和高通量化学分析法。高通量生物分析法最佳的检测条件为：25μl一定浓度的红霉素待测样品添加到225μ1检测培养基中,检测培养基接种5%菌悬液在37-C培养5h后,酶标仪580nm处检测。只需微升级样品,即可准确检测出低浓度产物。与管碟法、HPLC及化学显色法检测结果相比,相关系数依次为0.975,0.976,0.968。高通量化学分析法的建立需要考察样品前处理中的3个改变：反应介质的材料变化、反应体积的变化、脱水剂的变化,统计结果显示相对标准偏差均小于5%,说明样品前处理的3个改变不影响测定结果。高通量化学测定方法经可信度检定其相对标准偏差为0.324%,证明此方法充分可信。
最后,以红曲色素生产菌红曲霉为研究对象构建了高通量菌种筛选模型,获得高产菌株D39-4,摇瓶产量为206.5U/ml；为进一步提高高产菌株D39-4红曲色素的产量,结合响应面分析软件,建立了培养基的高通量筛选。与优化前的发酵培养基相比,红曲色素摇瓶发酵产量达到265.8U/ml,提高了近1.3倍,而副产物橘霉素产量变化不明显。培养基的高通量筛选解决了传统培养基优化设计时通量的限制,提高了实验准确度和精密度。
论文不仅建立了高通量筛选方法,还设计了与之配套的筛选装置,包括多种类型的深孔板及与其对应的具有通气、抗孔板间交叉污染的三明治盖板等,可供不同的产品建立独特的高通量筛选模型。红色糖多孢菌和红曲霉的高通量筛选技术的辐射应用,不仅验证该筛选平台的准确性与实用性,更为进一步完善和拓展高通量筛选技术奠定了基础。
Improvement of microbial strains for the high-production of industrial products has been the hallmark of all commercial fermentation processes. The construction of high-throughput screening strategy was pivotal for industrial fermentation technology. In order to realize the scale down cultivation by using microtiter plates (MTP), computational fluid dynamics (CFD) was used to simulate and compare the water superficial velocity and shear force between microtiter plates and shake flask. We solved the key problems encountered in microculture for aerobic microorganism, such as oxygen transfer rate and mixing time. In this thesis, filamentous fungi Acremonium chrysogenum was used to establish the flexible and universal high-throughput screening platform, two other aerobic microorganisms Saccharopolyspora erythraea and Monascus purpureus were used to verify the accuracy, feasibility and extensibility of the established screening platform.
First, A.chrysogenum was employed to construct the high efficiency high-throughput screening strategy. The low probability was the big drawback existed in the traditional screening method. Therefore, the mixture cultivation was effectively proposed and used for the first time to realise the whole mutant library being screened after mutagenesis, which avoided those unselected mutants being unscreened. The high-yield mixture in one well of the microtiter plate was screened out first. The subsequent isolation of the desirable high-yield colonies was further selected and screened from the high-yield mixture. This new screening approach greatly increased probability of obtaining the high-yield strain compared with the conventional method, by which only the parts of treated suspension had chance to be screened by tranditional dilution-plate method. As a result, the high-yield strain W-6was successfully screened out and the cephalosporin C (CPC) titer was nearly two-fold higher than that of the wild strain in50L bioreactor. In order to decipher the mechanism of high yield strain, the performance of the two strains were compared and analysed from the perspective of metabolic properties, mycelium morphology, enzymology, transcription and metabolic flux analysis based on multi-scale study approach. Glucose-6-phosphate dehydrogenase, citrate synthase, isocitrate lyase and malate synthetase are the four key enzymes involved in the primary metabolism. Their enzyme activities were analysed and compared between two strains.The results showed that the higher activities of isocitrate lyase and malate synthetase in primary metabolism might be the reason leading to the high yield of CPC production. Therefore, it can be speculated that the glyoxylate cycle played a pivotal role in the increasement of the metabolic flux leading to CPC biosynthesis, when soybean oil was added. ACV synthetase, expandase/hydroxylase and acetyltransferase were three important enzymes involved in CPC synthesis The genes encoding these three enzymes were pcbAB, cefEF and cefG perspectively. The transcription level of these three genes was compared between strain W-6and1-D1. The mRNA transcriptional levels of pcbAB, cefEF and cefG of W-6was5,8,1.2times of1-D1at72h,5,14,1.5times of1-D1at96h and4,50,7times of1-D1at120h. The results revealed that cefEF encoding expandase/hydroxylase might be the most important gene affecting CPC biosynthesis. The metabolic flux analysis indicated that glyoxylate cycle of high-yield strain was43%higher than the parent strain, so more oxaloacetic acid could be generated and entered into the replenishment pathway, which provided more NADPH and precursor amino acid for CPC synthesis.
Second, a rapid high-throughput microplate bioassay based on turbidimetry was developed for erythromycin quantification in the fermentation broth. The optimum detection conditions were obtained as follows:25μl certain concentration of samples were added into the225μl bioactivity assay medium mixed with5%inoculation volume of indicator bacteria suspension(OD1.5), incubated for5h at37℃. Thousands of samples could be determined simultaneously. Meanwhile, another rapid high-throughput assay based on colorimetric was established for the measurement of erythromycin chemical titer. The material of reaction medium, reaction volume and dehydrating agent were the three differences existed between microassay and colorimetric, but did not affect the outcome.
Last, a simple high-throughput screening system was developed for medium optimization. Strain D39-4was screened out and the pigment production was265.8U/ml fermented in shake flask. This high-throughput screening approach was designed to optimize medium composition combined with statistical methods. The analysis revealed that the optimum concentrations of glucose, peptone, NaNO3, KH2P04were51.42,4.91,1.00,1.00g/L. The fermentation medium optimized was verified in shake flasks, the pigment production could be enhanced from206.5U/ml in un-optimized medium to265.8U/ml, giving nearly1.30-fold increase in production.
In the paper, we also designed the screening device matched to high-throughput technology, included various kinds MTPs and corresponding'sandwich'lids to guarantee the minimization of fluid evaporation rate while maintain suitable aeration and gas exchange rate without cross-contamination. Different productions could select different device to construct their own high-throughput screening platform. We believe that the HTS field continues to be promising and dynamic in the future.
首先以顶头孢霉为研究对象,建立了提高筛选效率防止漏筛的高通量菌种筛选方法。即将所有诱变后孢子悬液等分至深孔板,同时培养与检测,先筛选出具有高产特性的存在于孔板中某一深孔中的混合菌群,再进一步从中分离纯化获得高产菌株。所构建的高通量筛选方法提供给诱变株平等的筛选机会,有效克服了传统筛选的漏筛问题。将此高通量筛选方法成功应用于头孢菌素C (CPC)高产菌株筛选,成功获得了一株顶头孢霉高产菌株W-6,在50L发酵罐上CPC产量比出发菌株1-D1提高了近2倍。接着开展了基于多尺度创新原理的菌种筛选后技术的系统研究,分别从代谢特性、菌形变化规律、酶学分析、与CPC合成相关的重要基因转录水平及定量代谢流分析等角度对获得的高产菌株与出发菌株进行了系统分析比较,初步揭示了高产菌株的高产机理。其中,酶学水平上,比较了两菌株在初级代谢过程中的四种关键酶酶活,分别是葡萄糖-6-磷酸脱氢酶、柠檬酸合成酶、异柠檬酸裂解酶和苹果酸合成酶。结果表明高产菌株的异柠檬酸裂解酶和苹果酸合成酶活性明显提高,因此在补加豆油的情况下,乙醛酸循环途径活性的明显提高是导致CPC产量提高的重要原因。我们还对CPC合成途径中的关键酶ACV合成酶、扩环酶/羟化酶、酰基转移酶的编码基因pcbAB, cefEF和cefG进行了转录水平的比较。高产菌株W-6的pcbAB、cefEF、cefG在72h的mRNA转录水平分别是出发菌株(1-D1)的5、8、1.2倍；在96h分别是1-D1的5、14、1.5倍；在120h分别是1-D1的4、50、7倍。说明进入CPC合成期后cefEF转录差异最大,扩环酶/羟化酶的限制很可能是影响CPC合成增加的重要原因,从而为进一步基因改造或优化培养条件提供了有益线索。代谢流计算结果表明,顶头孢霉菌丝体内的碳主要是在以柠檬酸循环、乙醛酸循环和回补途径进行代谢,高产菌株消耗的豆油总量较多,经过代谢分解成的C2底物浓度较高,导致其TCA循环通量较大。高产菌株W-6进入乙醛酸循环途径中的C2底物的通量是出发菌株的1.43倍,能够生成更多的草酰乙酸进入到回补途径当中去,供给CPC合成所需要的NADPH以及前体氨基酸。
其次,以红曲霉生产菌红色糖多孢菌为研究对象建立了每次检测通量可达数千的高通量生物分析法和高通量化学分析法。高通量生物分析法最佳的检测条件为：25μl一定浓度的红霉素待测样品添加到225μ1检测培养基中,检测培养基接种5%菌悬液在37-C培养5h后,酶标仪580nm处检测。只需微升级样品,即可准确检测出低浓度产物。与管碟法、HPLC及化学显色法检测结果相比,相关系数依次为0.975,0.976,0.968。高通量化学分析法的建立需要考察样品前处理中的3个改变：反应介质的材料变化、反应体积的变化、脱水剂的变化,统计结果显示相对标准偏差均小于5%,说明样品前处理的3个改变不影响测定结果。高通量化学测定方法经可信度检定其相对标准偏差为0.324%,证明此方法充分可信。
最后,以红曲色素生产菌红曲霉为研究对象构建了高通量菌种筛选模型,获得高产菌株D39-4,摇瓶产量为206.5U/ml；为进一步提高高产菌株D39-4红曲色素的产量,结合响应面分析软件,建立了培养基的高通量筛选。与优化前的发酵培养基相比,红曲色素摇瓶发酵产量达到265.8U/ml,提高了近1.3倍,而副产物橘霉素产量变化不明显。培养基的高通量筛选解决了传统培养基优化设计时通量的限制,提高了实验准确度和精密度。
论文不仅建立了高通量筛选方法,还设计了与之配套的筛选装置,包括多种类型的深孔板及与其对应的具有通气、抗孔板间交叉污染的三明治盖板等,可供不同的产品建立独特的高通量筛选模型。红色糖多孢菌和红曲霉的高通量筛选技术的辐射应用,不仅验证该筛选平台的准确性与实用性,更为进一步完善和拓展高通量筛选技术奠定了基础。
Improvement of microbial strains for the high-production of industrial products has been the hallmark of all commercial fermentation processes. The construction of high-throughput screening strategy was pivotal for industrial fermentation technology. In order to realize the scale down cultivation by using microtiter plates (MTP), computational fluid dynamics (CFD) was used to simulate and compare the water superficial velocity and shear force between microtiter plates and shake flask. We solved the key problems encountered in microculture for aerobic microorganism, such as oxygen transfer rate and mixing time. In this thesis, filamentous fungi Acremonium chrysogenum was used to establish the flexible and universal high-throughput screening platform, two other aerobic microorganisms Saccharopolyspora erythraea and Monascus purpureus were used to verify the accuracy, feasibility and extensibility of the established screening platform.
First, A.chrysogenum was employed to construct the high efficiency high-throughput screening strategy. The low probability was the big drawback existed in the traditional screening method. Therefore, the mixture cultivation was effectively proposed and used for the first time to realise the whole mutant library being screened after mutagenesis, which avoided those unselected mutants being unscreened. The high-yield mixture in one well of the microtiter plate was screened out first. The subsequent isolation of the desirable high-yield colonies was further selected and screened from the high-yield mixture. This new screening approach greatly increased probability of obtaining the high-yield strain compared with the conventional method, by which only the parts of treated suspension had chance to be screened by tranditional dilution-plate method. As a result, the high-yield strain W-6was successfully screened out and the cephalosporin C (CPC) titer was nearly two-fold higher than that of the wild strain in50L bioreactor. In order to decipher the mechanism of high yield strain, the performance of the two strains were compared and analysed from the perspective of metabolic properties, mycelium morphology, enzymology, transcription and metabolic flux analysis based on multi-scale study approach. Glucose-6-phosphate dehydrogenase, citrate synthase, isocitrate lyase and malate synthetase are the four key enzymes involved in the primary metabolism. Their enzyme activities were analysed and compared between two strains.The results showed that the higher activities of isocitrate lyase and malate synthetase in primary metabolism might be the reason leading to the high yield of CPC production. Therefore, it can be speculated that the glyoxylate cycle played a pivotal role in the increasement of the metabolic flux leading to CPC biosynthesis, when soybean oil was added. ACV synthetase, expandase/hydroxylase and acetyltransferase were three important enzymes involved in CPC synthesis The genes encoding these three enzymes were pcbAB, cefEF and cefG perspectively. The transcription level of these three genes was compared between strain W-6and1-D1. The mRNA transcriptional levels of pcbAB, cefEF and cefG of W-6was5,8,1.2times of1-D1at72h,5,14,1.5times of1-D1at96h and4,50,7times of1-D1at120h. The results revealed that cefEF encoding expandase/hydroxylase might be the most important gene affecting CPC biosynthesis. The metabolic flux analysis indicated that glyoxylate cycle of high-yield strain was43%higher than the parent strain, so more oxaloacetic acid could be generated and entered into the replenishment pathway, which provided more NADPH and precursor amino acid for CPC synthesis.
Second, a rapid high-throughput microplate bioassay based on turbidimetry was developed for erythromycin quantification in the fermentation broth. The optimum detection conditions were obtained as follows:25μl certain concentration of samples were added into the225μl bioactivity assay medium mixed with5%inoculation volume of indicator bacteria suspension(OD1.5), incubated for5h at37℃. Thousands of samples could be determined simultaneously. Meanwhile, another rapid high-throughput assay based on colorimetric was established for the measurement of erythromycin chemical titer. The material of reaction medium, reaction volume and dehydrating agent were the three differences existed between microassay and colorimetric, but did not affect the outcome.
Last, a simple high-throughput screening system was developed for medium optimization. Strain D39-4was screened out and the pigment production was265.8U/ml fermented in shake flask. This high-throughput screening approach was designed to optimize medium composition combined with statistical methods. The analysis revealed that the optimum concentrations of glucose, peptone, NaNO3, KH2P04were51.42,4.91,1.00,1.00g/L. The fermentation medium optimized was verified in shake flasks, the pigment production could be enhanced from206.5U/ml in un-optimized medium to265.8U/ml, giving nearly1.30-fold increase in production.
In the paper, we also designed the screening device matched to high-throughput technology, included various kinds MTPs and corresponding'sandwich'lids to guarantee the minimization of fluid evaporation rate while maintain suitable aeration and gas exchange rate without cross-contamination. Different productions could select different device to construct their own high-throughput screening platform. We believe that the HTS field continues to be promising and dynamic in the future.
引文
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