Research Advances in the Enhancement of Microbial Tolerance to Acid Stress

doi:10.13560/j.cnki.biotech.bull.1985.2023-0686

Abstract

Abstract:

Microorganisms are often exposed to accumulation of various acidic substances during the fermentation process, which can seriously inhibit fermentation activity and production performance of the strains. Therefore, microorganisms have formed complex response mechanisms for the adaptation of low pH stress by coordinating cellular multiple physiological systems, metabolic pathways and regulatory network during the long-term evolution. The acid tolerance enhancement of the industrial microorganisms is a key way to improve its production efficiency. This review summarizes the recent research advances in the improvement on cell resistance to acids by the adaptive laboratory evolution, pre-adaptation, genome shuffling, genetic engineering, the global transcription machinery engineering, system biology and synthetic biology. The challenges and outlook of the relevant research are also discussed.

Key words: microorganisms, acid stress, tolerance enhancement, strain modification, gene circuit

HU Jin-chao, SHEN Wen-qi, XU Chao-ye, FAN Ya-qi, LU Hao-yu, JIANG Wen-jie, LI Shi-long, JIN Hong-chen, LUO Jian-mei, WANG Min. Research Advances in the Enhancement of Microbial Tolerance to Acid Stress[J]. Biotechnology Bulletin, 2023, 39(11): 137-149.

Figures/Tables 8

References 63

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改造策略Modification strategy	优点Advantages	缺点Disadvantages
适应性实验室进化	不需要了解菌株遗传信息、不依赖分子操作工具，可积累丰富的有益突变体	改造周期长、进化结果有一定随机性
预适应	耗时较短，可实现多种胁迫耐受性的交叉保护	适应结果随机性大，优良性状不稳定
基因组重排	不需要了解菌株遗传信息，不依赖分子操作工具，有利于多种优良性状的集合	对亲本菌株的质量要求较高，重排过程具有随机性，筛选过程费时费力
基因工程改造	靶向性高，便捷快速	高度依赖菌株的遗传背景和分子操作工具
全局转录机制工程	操作靶点少，能引发胞内的全局变化，适合复杂表型的改善	大量全局转录因子尚未被开发，改造靶向性差，筛选工作量大
系统生物学	改造通量大，可研究多个基因的协同作用，提升效果明显	多个基因的同时操作容易增加细胞的生理代谢负担
合成生物学	可根据环境变化对基因表达进行动态调控，减小细胞代谢负担	调控元件的挖掘不够广泛，复杂基因线路的导入可能与宿主代谢网络之间形成串扰

改造策略Modification strategy	优点Advantages	缺点Disadvantages
适应性实验室进化	不需要了解菌株遗传信息、不依赖分子操作工具，可积累丰富的有益突变体	改造周期长、进化结果有一定随机性
预适应	耗时较短，可实现多种胁迫耐受性的交叉保护	适应结果随机性大，优良性状不稳定
基因组重排	不需要了解菌株遗传信息，不依赖分子操作工具，有利于多种优良性状的集合	对亲本菌株的质量要求较高，重排过程具有随机性，筛选过程费时费力
基因工程改造	靶向性高，便捷快速	高度依赖菌株的遗传背景和分子操作工具
全局转录机制工程	操作靶点少，能引发胞内的全局变化，适合复杂表型的改善	大量全局转录因子尚未被开发，改造靶向性差，筛选工作量大
系统生物学	改造通量大，可研究多个基因的协同作用，提升效果明显	多个基因的同时操作容易增加细胞的生理代谢负担
合成生物学	可根据环境变化对基因表达进行动态调控，减小细胞代谢负担	调控元件的挖掘不够广泛，复杂基因线路的导入可能与宿主代谢网络之间形成串扰

菌株Strain	靶点Targets	提升效果Improving effect	参考文献Reference
大肠杆菌 Escherichia coli	氢化酶辅助蛋白HypB和HypC	乳酸产量提高2.1倍	[5]
解脂耶氏酵母 Yarrowia lipolytica	多效耐药蛋白 E25201g、膜组成蛋白 F16731g, B18854g、主要促进超家族渗透酶 F05984g	阿魏酸耐受性从0.5 g/L提高到1.5 g/L	[17]
恶臭假单胞菌 Pseudomonas putida	谷氨酸脱羧酶GadBC	pH 4.0下最终OD₆₀₀提高30%以上	[31]
大肠杆菌E. coli	甲型流感基质-2（M2）蛋白	乙酸、庚酸、蓖麻油酸胁迫后CFU提高26.0%-65.0%	[32]
植物乳杆菌 Lactobacillus plantarum	硫氧还原蛋白TrxA	pH 3.4下最终OD₆₀₀提高40%左右	[33]
植物乳杆菌L. plantarum	转录因子CtsR	酸-乙醇条件下最终OD₆₀₀提高10%以上	[34]
大肠杆菌E. coli	转录因子H-NS	pH 2.5下存活性能提高100倍，pH 5.35乙酸和pH 5.35琥珀酸下生长性能提高30%和20%左右	[35]
大肠杆菌E. coli	过氧化氢酶KatE和超氧化物歧化酶SodB	乙酰丙酸产量提高117.0%	[36]
酿酒酵母 Saccharomyces cerevisiae	转录因子Haa1和磷酸核糖基焦磷酸合成酶PRS3	乙酸胁迫下葡萄糖消耗时间缩短70%	[37]
大肠杆菌E. coli	整合宿主因子α亚基 IhfA、谷氨酸脱羧酶 GadA、DNA 修复蛋白 AidB 以及膜损伤蛋白 RyfA	脂肪酸产量提高360%	[38]
大肠杆菌E. coli	小分子RNA DsrA，分子伴侣Hfq	pH 2.5和pH4.5下存活率和最终OD₆₀₀分别提高100倍和72%	[39]
巴氏醋杆菌 Acetobacter pasteurianus	乙酰辅酶A合酶ACS1	乙酸产量提高153%	[42]
酿酒酵母S. cerevisiae	乙酰辅酶A合酶ACS1	乙醇产量提高约10%	[43]
大肠杆菌E. coli	周质伴侣HdeB、抗氧化酶SodB和KatE	pH 5.0下最终OD₆₀₀提高57.0%	[44]

菌株Strain	靶点Targets	提升效果Improving effect	参考文献Reference
大肠杆菌 Escherichia coli	氢化酶辅助蛋白HypB和HypC	乳酸产量提高2.1倍	[5]
解脂耶氏酵母 Yarrowia lipolytica	多效耐药蛋白 E25201g、膜组成蛋白 F16731g, B18854g、主要促进超家族渗透酶 F05984g	阿魏酸耐受性从0.5 g/L提高到1.5 g/L	[17]
恶臭假单胞菌 Pseudomonas putida	谷氨酸脱羧酶GadBC	pH 4.0下最终OD₆₀₀提高30%以上	[31]
大肠杆菌E. coli	甲型流感基质-2（M2）蛋白	乙酸、庚酸、蓖麻油酸胁迫后CFU提高26.0%-65.0%	[32]
植物乳杆菌 Lactobacillus plantarum	硫氧还原蛋白TrxA	pH 3.4下最终OD₆₀₀提高40%左右	[33]
植物乳杆菌L. plantarum	转录因子CtsR	酸-乙醇条件下最终OD₆₀₀提高10%以上	[34]
大肠杆菌E. coli	转录因子H-NS	pH 2.5下存活性能提高100倍，pH 5.35乙酸和pH 5.35琥珀酸下生长性能提高30%和20%左右	[35]
大肠杆菌E. coli	过氧化氢酶KatE和超氧化物歧化酶SodB	乙酰丙酸产量提高117.0%	[36]
酿酒酵母 Saccharomyces cerevisiae	转录因子Haa1和磷酸核糖基焦磷酸合成酶PRS3	乙酸胁迫下葡萄糖消耗时间缩短70%	[37]
大肠杆菌E. coli	整合宿主因子α亚基 IhfA、谷氨酸脱羧酶 GadA、DNA 修复蛋白 AidB 以及膜损伤蛋白 RyfA	脂肪酸产量提高360%	[38]
大肠杆菌E. coli	小分子RNA DsrA，分子伴侣Hfq	pH 2.5和pH4.5下存活率和最终OD₆₀₀分别提高100倍和72%	[39]
巴氏醋杆菌 Acetobacter pasteurianus	乙酰辅酶A合酶ACS1	乙酸产量提高153%	[42]
酿酒酵母S. cerevisiae	乙酰辅酶A合酶ACS1	乙醇产量提高约10%	[43]
大肠杆菌E. coli	周质伴侣HdeB、抗氧化酶SodB和KatE	pH 5.0下最终OD₆₀₀提高57.0%	[44]