合成微生物组:当“合成生物学”遇见“微生物组学”
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摘要
合成微生物组是指运用合成生物学方法构建的功能菌群.合成微生物组以代谢通路模块化为核心特征,每个代谢模块的工作由一个菌株完成,从而实现多个菌株的分工与合作.与单菌株相比,合成微生物组具有降低菌株代谢负担与遗传改造难度、提供多样的元件表达平台、实现"即插即用"的模块替换等优势.在合成生物学与微生物组学快速发展、交汇融合的影响下,合成微生物组已成为近些年微生物领域新的研究热点,在生物合成平台化合物、复杂大分子以及生产生物燃料等方面具有广阔的应用前景.本文介绍了合成微生物组的设计原理与优势,总结了近些年的主要研究成果,阐述其目前面临的挑战与机遇,最后对其未来的发展进行展望.
Microbiomics focuses on the composition and function of microbial communities in a specific environment, while synthetic biology is an emerging discipline that uses engineering principles to elucidate, simulate and construct biological systems. The interdisciplinary branch of these disciplines has developed into an emerging subject called synthetic microbiomics, which has become a topic of interest in the field of microbiology. Distinct from the traditional functional microbiome, the synthetic microbiome refers to the functional microbiota constructed under the guidance of synthetic biology instead of the natural microbiota. The construction of a synthetic microbiome involves several steps, including model design, strain engineering, evaluation and optimization.Characterized by the modularization of metabolic pathways, the synthetic microbiome actualizes the cooperation of multiple strains with different functions. The synthetic microbiome has several advantages over monoculture in the case of synthesizing complex macromolecules and other platform chemicals. First, the metabolic burden of each strain is reduced as well as the difficulty of plasmid construction. Second, varied expression platforms are provided for multiple modules to increase the expression level of heterologous proteins. Third, modules could be easily added or substituted to obtain diverse products, and the relative metabolic intensity of each module is controlled through the inoculation ratio of co-cultured strains. Meanwhile, different parts of metabolic pathways are insulated by cell membrane, reducing the yield of byproducts. Finally, mixed substrates, such as lignocellulose hydrolysates, can be efficiently utilized by multiple strains,which cannot be used by a single strain due to substrate preference.Research on the synthetic microbiome has increased in recent years, yet most of these findings have not been applied in industry. The applications of the synthetic microbiome are normally concentrated on the production of three categories of products: platform compounds, complex macromolecules and biofuels. Other applications, such as bioelectrochemical systems and light-driven consortia, offer new energy resources and have significance in fundamental research on the symbiotic relationship of co-cultured strains. In many cases, the yield has remarkably improved thanks to the decrease of metabolic burdens caused by the division of labour. However, the stability and robustness of synthetic microbiomes remain as challenges. To improve stability, two design strategies could be taken into consideration: The quorum sensing system and the cross-feeding system. Improvements in genetic engineering and substrate utilization will enhance robustness. With the development of synthetic biology, more genetic editing and regulation tools will come into use, providing the possibility to construct stable and robust synthetic microbiomes comprising more strains. Once stability and robustness are attained, synthetic microbiome applications will likely spread throughout industry.
Microbiomics focuses on the composition and function of microbial communities in a specific environment, while synthetic biology is an emerging discipline that uses engineering principles to elucidate, simulate and construct biological systems. The interdisciplinary branch of these disciplines has developed into an emerging subject called synthetic microbiomics, which has become a topic of interest in the field of microbiology. Distinct from the traditional functional microbiome, the synthetic microbiome refers to the functional microbiota constructed under the guidance of synthetic biology instead of the natural microbiota. The construction of a synthetic microbiome involves several steps, including model design, strain engineering, evaluation and optimization.Characterized by the modularization of metabolic pathways, the synthetic microbiome actualizes the cooperation of multiple strains with different functions. The synthetic microbiome has several advantages over monoculture in the case of synthesizing complex macromolecules and other platform chemicals. First, the metabolic burden of each strain is reduced as well as the difficulty of plasmid construction. Second, varied expression platforms are provided for multiple modules to increase the expression level of heterologous proteins. Third, modules could be easily added or substituted to obtain diverse products, and the relative metabolic intensity of each module is controlled through the inoculation ratio of co-cultured strains. Meanwhile, different parts of metabolic pathways are insulated by cell membrane, reducing the yield of byproducts. Finally, mixed substrates, such as lignocellulose hydrolysates, can be efficiently utilized by multiple strains,which cannot be used by a single strain due to substrate preference.Research on the synthetic microbiome has increased in recent years, yet most of these findings have not been applied in industry. The applications of the synthetic microbiome are normally concentrated on the production of three categories of products: platform compounds, complex macromolecules and biofuels. Other applications, such as bioelectrochemical systems and light-driven consortia, offer new energy resources and have significance in fundamental research on the symbiotic relationship of co-cultured strains. In many cases, the yield has remarkably improved thanks to the decrease of metabolic burdens caused by the division of labour. However, the stability and robustness of synthetic microbiomes remain as challenges. To improve stability, two design strategies could be taken into consideration: The quorum sensing system and the cross-feeding system. Improvements in genetic engineering and substrate utilization will enhance robustness. With the development of synthetic biology, more genetic editing and regulation tools will come into use, providing the possibility to construct stable and robust synthetic microbiomes comprising more strains. Once stability and robustness are attained, synthetic microbiome applications will likely spread throughout industry.
引文
1 Liu S J,Shi W Y,Zhao G P.China microbiome initiative:Opportunity and challenges(in Chinese).Bull Chin Acad Sci,2017,32:241-250[刘双江,施文元,赵国屏.中国微生物组计划:机遇与挑战.中国科学院院刊,2017,32:241-250]
2 Purnick P E M,Weiss R.The second wave of synthetic biology:From modules to systems.Nat Rev Mol Cell Biol,2009,10:410-422
3 Ortiz-Marquez J C F,Do Nascimento M,Zehr J P,et al.Genetic engineering of multispecies microbial cell factories as an alternative for bioenergy production.Trends Biotech,2013,31:521-529
4 Jia X,Liu C,Song H,et al.Design,analysis and application of synthetic microbial consortia.Synth Syst Biotech,2016,1:109-117
5 Schindler D,Dai J,Cai Y.Synthetic genomics:A new venture to dissect genome fundamentals and engineer new functions.Curr Opin Chem Biol,2018,46:56-62
6 Wang L,Jiang S,Chen C,et al.Synthetic genomics:From DNA synthesis to genome design.Angew Chem Int Ed,2018,57:1748-1756
7 Sabra W,Dietz D,Tjahjasari D,et al.Biosystems analysis and engineering of microbial consortia for industrial biotechnology.Eng Life Sci,2010,10:407-421
8 Zou W,Liu L,Chen J.Structure,mechanism and regulation of an artificial microbial ecosystem for vitamin C production.Critical Rev MicroBiol,2012,39:247-255
9 Du J,Zhou J,Xue J,et al.Metabolomic profiling elucidates community dynamics of the Ketogulonicigenium vulgare-Bacillus megaterium consortium.Metabolomics,2012,8:960-973
10 Ye C,Zou W,Xu N,et al.Metabolic model reconstruction and analysis of an artificial microbial ecosystem for vitamin C production.J Biotechnol,2014,182:61-67
11 Lakshmanan V,Selvaraj G,Bais H P.Functional soil microbiome:Belowground solutions to an aboveground problem.Plant Physiol,2014,166:689-700
12 Bader J,Mast-Gerlach E,Popovi?M K,et al.Relevance of microbial coculture fermentations in biotechnology.J Appl Microbiol,2010,109:371-387
13 Zhang H,Wang X.Modular co-culture engineering,a new approach for metabolic engineering.Metabolic Eng,2016,37:114-121
14 Ding M Z,Song H,Wang E X,et al.Design and construction of synthetic microbial consortia in China.Synth Syst Biotech,2016,1:230-235
15 Pandhal J,Noirel J.Synthetic microbial ecosystems for biotechnology.Biotechnol Lett,2014,36:1141-1151
16 Wang E X,Ding M Z,Ma Q,et al.Reorganization of a synthetic microbial consortium for one-step vitamin C fermentation.Microb Cell Fact,2016,15:21
17 Jones J A,Vernacchio V R,Collins S M,et al.Complete biosynthesis of anthocyanins using E.coli polycultures.mBio,2017,8:e00621-17
18 Zhang H,Stephanopoulos G.Co-culture engineering for microbial biosynthesis of 3-amino-benzoic acid in Escherichia coli.Biotech J,2016,11:981-987
19 Zuroff T R,Barri Xiques S,Curtis W R.Consortia-mediated bioprocessing of cellulose to ethanol with a symbiotic Clostridium phytofermentans/yeast co-culture.Biotechnol Biofuels,2013,6:59
20 Bayer T S,Widmaier D M,Temme K,et al.Synthesis of methyl halides from biomass using engineered microbes.J Am Chem Soc,2009,131:6508-6515
21 Zhou K,Qiao K,Edgar S,et al.Distributing a metabolic pathway among a microbial consortium enhances production of natural products.Nat Biotechnol,2015,33:377-383
22 Ahmadi M K,Fang L,Moscatello N,et al.E.coli Metabolic Engineering for gram scale production of a plant-based anti-inflammatory agent.Metabolic Eng,2016,38:382-388
23 Jones J A,Vernacchio V R,Sinkoe A L,et al.Experimental and computational optimization of an Escherichia coli co-culture for the efficient production of flavonoids.Metabolic Eng,2016,35:55-63
24 Chen Z,Sun X,Li Y,et al.Metabolic Engineering of Escherichia coli for microbial synthesis of monolignols.Metabolic Eng,2017,39:102-109
25 Zhang H,Pereira B,Li Z,et al.Engineering Escherichia coli coculture systems for the production of biochemical products.Proc Natl Acad Sci USA,2015,112:8266-8271
26 Brenner K,You L,Arnold F H.Engineering microbial consortia:A new frontier in synthetic biology.Trends Biotech,2008,26:483-489
27 Zhang H,Li Z,Pereira B,et al.Engineering E.coli-E.coli cocultures for production of muconic acid from glycerol.Microb Cell Fact,2015,14:134
28 Ganesan V,Li Z,Wang X,et al.Heterologous biosynthesis of natural product naringenin by co-culture engineering.Synth Syst Biotech,2017,2:236-242
29 Liu Y,Tu X,Xu Q,et al.Engineered monoculture and co-culture of methylotrophic yeast for de novo production of monacolin J and lovastatin from methanol.Metabolic Eng,2018,45:189-199
30 Weiss T L,Young E J,Ducat D C.A synthetic,light-driven consortium of cyanobacteria and heterotrophic bacteria enables stable polyhydroxybutyrate production.Metabolic Eng,2017,44:236-245
31 Liu Y,Ding M,Ling W,et al.A three-species microbial consortium for power generation.Energy Environ Sci,2017,10:1600-1609
32 Liu T,Yu Y Y,Chen T,et al.A synthetic microbial consortium of Shewanella and Bacillus for enhanced generation of bioelectricity.Biotechnol Bioeng,2017,114:526-532
33 Lin T,Bai X,Hu Y,et al.Synthetic Saccharomyces cerevisiae-Shewanella oneidensis consortium enables glucose-fed high-performance microbial fuel cell.AIChE J,2017,63:1830-1838
34 Chen Y.Development and application of co-culture for ethanol production by co-fermentation of glucose and xylose:A systematic review.J Ind Microbiol Biotechnol,2011,38:581-597
35 Jagmann N,Philipp B.Design of synthetic microbial communities for biotechnological production processes.J Biotech,2014,184:209-218
36 Kleerebezem R,van Loosdrecht M C M.Mixed culture biotechnology for bioenergy production.Curr Opin Biotech,2007,18:207-212
37 Puentes-Téllez P E,Falcao Salles J.Construction of effective minimal active microbial consortia for lignocellulose degradation.Microb Ecol,2018,76:419-429
38 Jiménez D J,Chaib De Mares M,Salles J F.Temporal expression dynamics of plant biomass-degrading enzymes by a synthetic bacterial consortium growing on Sugarcane Bagasse.Front Microbiol,2018,9:299
39 Wen Z,Minton N P,Zhang Y,et al.Enhanced solvent production by Metabolic Engineering of a twin-clostridial consortium.Metabolic Eng,2017,39:38-48
40 Valdez-Vazquez I,Pérez-Rangel M,Tapia A,et al.Hydrogen and butanol production from native wheat straw by synthetic microbial consortia integrated by species of Enterococcus and Clostridium.Fuel,2015,159:214-222
41 Nakayama S,Kiyoshi K,Kadokura T,et al.Butanol production from crystalline cellulose by cocultured Clostridium thermocellum and Clostridium saccharoperbutylacetonicum N1-4.Appl Environ Microbiol,2011,77:6470-6475
42 Saini M,Chiang C J,Li S Y,et al.Production of biobutanol from cellulose hydrolysate by the Escherichia coli co-culture system.FEMS Microbiol Lett,2016,363:fnw008
43 Saini M,Chen M H,Chiang C J,et al.Potential production platform of n-butanol in Escherichia coli.Metabolic Eng,2015,27:76-82
44 Minty J J,Singer M E,Scholz S A,et al.Design and characterization of synthetic fungal-bacterial consortia for direct production of isobutanol from cellulosic biomass.Proc Natl Acad Sci USA,2013,110:14592-14597
45 Shin H D,McClendon S,Vo T,et al.Escherichia coli binary culture engineered for direct fermentation of hemicellulose to a biofuel.Appl Environ Microbiol,2010,76:8150-8159
46 Liu F,Wu W,Tran-Gyamfi M B,et al.Bioconversion of distillers’grains hydrolysates to advanced biofuels by an Escherichia coli co-culture.Microb Cell Fact,2017,16:192
47 Willrodt C,Hoschek A,Bühler B,et al.Coupling limonene formation and oxyfunctionalization by mixed-culture resting cell fermentation.Biotechnol Bioeng,2015,112:1738-1750
48 Fang Z,Jones J A,Zhou J,et al.Engineering Escherichia coli co-cultures for production of curcuminoids from glucose.Biotechnol J,2018,13:1700576
49 Minami H,Kim J S,Ikezawa N,et al.Microbial production of plant benzylisoquinoline alkaloids.Proc Natl Acad Sci USA,2008,105:7393-7398
50 Koizumi S,Endo T,Tabata K,et al.Large-scale production of UDP-galactose and globotriose by coupling metabolically engineered bacteria.Nat Biotechnol,1998,16:847-850
51 Goers L,Freemont P,Polizzi K M.Co-culture systems and technologies:Taking synthetic biology to the next level.J R Soc Interface,2014,11:20140065
52 Song H,Ding M Z,Jia X Q,et al.Synthetic microbial consortia:From systematic analysis to construction and applications.Chem Soc Rev,2014,43:6954-6981
53 Pan J,Ren D.Quorum sensing inhibitors:A patent overview.Expert Opin Therapeutic Patents,2009,19:1581-1601
54 Bassler B L.How bacteria talk to each other:Regulation of gene expression by quorum sensing.Curr Opin MicroBiol,1999,2:582-587
55 Scott S R,Din M O,Bittihn P,et al.A stabilized microbial ecosystem of self-limiting bacteria using synthetic quorum-regulated lysis.Nat Microbiol,2017,2:17083
56 Chan S H J,Simons M N,Maranas C D.SteadyCom:Predicting microbial abundances while ensuring community stability.PLoS Comput Biol,2017,13:e1005539
57 Mee M T,Collins J J,Church G M,et al.Syntrophic exchange in synthetic microbial communities.Proc Natl Acad Sci USA,2014,111:E2149-E2156
58 Johns N I,Blazejewski T,Gomes A L,et al.Principles for designing synthetic microbial communities.Curr Opin MicroBiol,2016,31:146-153
59 Sleight S C,Bartley B A,Lieviant J A,et al.Designing and engineering evolutionary robust genetic circuits.J Biol Eng,2010,4:12
60 Renda B A,Hammerling M J,Barrick J E.Engineering reduced evolutionary potential for synthetic biology.Mol BioSyst,2014,10:1668-1678
61 Villarreal F,Contreras-Llano L E,Chavez M,et al.Synthetic microbial consortia enable rapid assembly of pure translation machinery.Nat Chem Biol,2018,14:29-35
62 Grosskopf T,Soyer O S.Synthetic microbial communities.Curr Opin MicroBiol,2014,18:72-77
63 Peng X,Gilmore S P,O’Malley M A.Microbial communities for bioprocessing:Lessons learned from nature.Curr Opin Chem Eng,2016,14:103-109
64 Eng A,Borenstein E.An algorithm for designing minimal microbial communities with desired metabolic capacities.Bioinformatics,2016,32:2008-2016
65 Cortes-Tolalpa L,Salles J F,van Elsas J D.Bacterial synergism in lignocellulose biomass degradation-Complementary roles of degraders as influenced by complexity of the carbon source.Front Microbiol,2017,8:1628
2 Purnick P E M,Weiss R.The second wave of synthetic biology:From modules to systems.Nat Rev Mol Cell Biol,2009,10:410-422
3 Ortiz-Marquez J C F,Do Nascimento M,Zehr J P,et al.Genetic engineering of multispecies microbial cell factories as an alternative for bioenergy production.Trends Biotech,2013,31:521-529
4 Jia X,Liu C,Song H,et al.Design,analysis and application of synthetic microbial consortia.Synth Syst Biotech,2016,1:109-117
5 Schindler D,Dai J,Cai Y.Synthetic genomics:A new venture to dissect genome fundamentals and engineer new functions.Curr Opin Chem Biol,2018,46:56-62
6 Wang L,Jiang S,Chen C,et al.Synthetic genomics:From DNA synthesis to genome design.Angew Chem Int Ed,2018,57:1748-1756
7 Sabra W,Dietz D,Tjahjasari D,et al.Biosystems analysis and engineering of microbial consortia for industrial biotechnology.Eng Life Sci,2010,10:407-421
8 Zou W,Liu L,Chen J.Structure,mechanism and regulation of an artificial microbial ecosystem for vitamin C production.Critical Rev MicroBiol,2012,39:247-255
9 Du J,Zhou J,Xue J,et al.Metabolomic profiling elucidates community dynamics of the Ketogulonicigenium vulgare-Bacillus megaterium consortium.Metabolomics,2012,8:960-973
10 Ye C,Zou W,Xu N,et al.Metabolic model reconstruction and analysis of an artificial microbial ecosystem for vitamin C production.J Biotechnol,2014,182:61-67
11 Lakshmanan V,Selvaraj G,Bais H P.Functional soil microbiome:Belowground solutions to an aboveground problem.Plant Physiol,2014,166:689-700
12 Bader J,Mast-Gerlach E,Popovi?M K,et al.Relevance of microbial coculture fermentations in biotechnology.J Appl Microbiol,2010,109:371-387
13 Zhang H,Wang X.Modular co-culture engineering,a new approach for metabolic engineering.Metabolic Eng,2016,37:114-121
14 Ding M Z,Song H,Wang E X,et al.Design and construction of synthetic microbial consortia in China.Synth Syst Biotech,2016,1:230-235
15 Pandhal J,Noirel J.Synthetic microbial ecosystems for biotechnology.Biotechnol Lett,2014,36:1141-1151
16 Wang E X,Ding M Z,Ma Q,et al.Reorganization of a synthetic microbial consortium for one-step vitamin C fermentation.Microb Cell Fact,2016,15:21
17 Jones J A,Vernacchio V R,Collins S M,et al.Complete biosynthesis of anthocyanins using E.coli polycultures.mBio,2017,8:e00621-17
18 Zhang H,Stephanopoulos G.Co-culture engineering for microbial biosynthesis of 3-amino-benzoic acid in Escherichia coli.Biotech J,2016,11:981-987
19 Zuroff T R,Barri Xiques S,Curtis W R.Consortia-mediated bioprocessing of cellulose to ethanol with a symbiotic Clostridium phytofermentans/yeast co-culture.Biotechnol Biofuels,2013,6:59
20 Bayer T S,Widmaier D M,Temme K,et al.Synthesis of methyl halides from biomass using engineered microbes.J Am Chem Soc,2009,131:6508-6515
21 Zhou K,Qiao K,Edgar S,et al.Distributing a metabolic pathway among a microbial consortium enhances production of natural products.Nat Biotechnol,2015,33:377-383
22 Ahmadi M K,Fang L,Moscatello N,et al.E.coli Metabolic Engineering for gram scale production of a plant-based anti-inflammatory agent.Metabolic Eng,2016,38:382-388
23 Jones J A,Vernacchio V R,Sinkoe A L,et al.Experimental and computational optimization of an Escherichia coli co-culture for the efficient production of flavonoids.Metabolic Eng,2016,35:55-63
24 Chen Z,Sun X,Li Y,et al.Metabolic Engineering of Escherichia coli for microbial synthesis of monolignols.Metabolic Eng,2017,39:102-109
25 Zhang H,Pereira B,Li Z,et al.Engineering Escherichia coli coculture systems for the production of biochemical products.Proc Natl Acad Sci USA,2015,112:8266-8271
26 Brenner K,You L,Arnold F H.Engineering microbial consortia:A new frontier in synthetic biology.Trends Biotech,2008,26:483-489
27 Zhang H,Li Z,Pereira B,et al.Engineering E.coli-E.coli cocultures for production of muconic acid from glycerol.Microb Cell Fact,2015,14:134
28 Ganesan V,Li Z,Wang X,et al.Heterologous biosynthesis of natural product naringenin by co-culture engineering.Synth Syst Biotech,2017,2:236-242
29 Liu Y,Tu X,Xu Q,et al.Engineered monoculture and co-culture of methylotrophic yeast for de novo production of monacolin J and lovastatin from methanol.Metabolic Eng,2018,45:189-199
30 Weiss T L,Young E J,Ducat D C.A synthetic,light-driven consortium of cyanobacteria and heterotrophic bacteria enables stable polyhydroxybutyrate production.Metabolic Eng,2017,44:236-245
31 Liu Y,Ding M,Ling W,et al.A three-species microbial consortium for power generation.Energy Environ Sci,2017,10:1600-1609
32 Liu T,Yu Y Y,Chen T,et al.A synthetic microbial consortium of Shewanella and Bacillus for enhanced generation of bioelectricity.Biotechnol Bioeng,2017,114:526-532
33 Lin T,Bai X,Hu Y,et al.Synthetic Saccharomyces cerevisiae-Shewanella oneidensis consortium enables glucose-fed high-performance microbial fuel cell.AIChE J,2017,63:1830-1838
34 Chen Y.Development and application of co-culture for ethanol production by co-fermentation of glucose and xylose:A systematic review.J Ind Microbiol Biotechnol,2011,38:581-597
35 Jagmann N,Philipp B.Design of synthetic microbial communities for biotechnological production processes.J Biotech,2014,184:209-218
36 Kleerebezem R,van Loosdrecht M C M.Mixed culture biotechnology for bioenergy production.Curr Opin Biotech,2007,18:207-212
37 Puentes-Téllez P E,Falcao Salles J.Construction of effective minimal active microbial consortia for lignocellulose degradation.Microb Ecol,2018,76:419-429
38 Jiménez D J,Chaib De Mares M,Salles J F.Temporal expression dynamics of plant biomass-degrading enzymes by a synthetic bacterial consortium growing on Sugarcane Bagasse.Front Microbiol,2018,9:299
39 Wen Z,Minton N P,Zhang Y,et al.Enhanced solvent production by Metabolic Engineering of a twin-clostridial consortium.Metabolic Eng,2017,39:38-48
40 Valdez-Vazquez I,Pérez-Rangel M,Tapia A,et al.Hydrogen and butanol production from native wheat straw by synthetic microbial consortia integrated by species of Enterococcus and Clostridium.Fuel,2015,159:214-222
41 Nakayama S,Kiyoshi K,Kadokura T,et al.Butanol production from crystalline cellulose by cocultured Clostridium thermocellum and Clostridium saccharoperbutylacetonicum N1-4.Appl Environ Microbiol,2011,77:6470-6475
42 Saini M,Chiang C J,Li S Y,et al.Production of biobutanol from cellulose hydrolysate by the Escherichia coli co-culture system.FEMS Microbiol Lett,2016,363:fnw008
43 Saini M,Chen M H,Chiang C J,et al.Potential production platform of n-butanol in Escherichia coli.Metabolic Eng,2015,27:76-82
44 Minty J J,Singer M E,Scholz S A,et al.Design and characterization of synthetic fungal-bacterial consortia for direct production of isobutanol from cellulosic biomass.Proc Natl Acad Sci USA,2013,110:14592-14597
45 Shin H D,McClendon S,Vo T,et al.Escherichia coli binary culture engineered for direct fermentation of hemicellulose to a biofuel.Appl Environ Microbiol,2010,76:8150-8159
46 Liu F,Wu W,Tran-Gyamfi M B,et al.Bioconversion of distillers’grains hydrolysates to advanced biofuels by an Escherichia coli co-culture.Microb Cell Fact,2017,16:192
47 Willrodt C,Hoschek A,Bühler B,et al.Coupling limonene formation and oxyfunctionalization by mixed-culture resting cell fermentation.Biotechnol Bioeng,2015,112:1738-1750
48 Fang Z,Jones J A,Zhou J,et al.Engineering Escherichia coli co-cultures for production of curcuminoids from glucose.Biotechnol J,2018,13:1700576
49 Minami H,Kim J S,Ikezawa N,et al.Microbial production of plant benzylisoquinoline alkaloids.Proc Natl Acad Sci USA,2008,105:7393-7398
50 Koizumi S,Endo T,Tabata K,et al.Large-scale production of UDP-galactose and globotriose by coupling metabolically engineered bacteria.Nat Biotechnol,1998,16:847-850
51 Goers L,Freemont P,Polizzi K M.Co-culture systems and technologies:Taking synthetic biology to the next level.J R Soc Interface,2014,11:20140065
52 Song H,Ding M Z,Jia X Q,et al.Synthetic microbial consortia:From systematic analysis to construction and applications.Chem Soc Rev,2014,43:6954-6981
53 Pan J,Ren D.Quorum sensing inhibitors:A patent overview.Expert Opin Therapeutic Patents,2009,19:1581-1601
54 Bassler B L.How bacteria talk to each other:Regulation of gene expression by quorum sensing.Curr Opin MicroBiol,1999,2:582-587
55 Scott S R,Din M O,Bittihn P,et al.A stabilized microbial ecosystem of self-limiting bacteria using synthetic quorum-regulated lysis.Nat Microbiol,2017,2:17083
56 Chan S H J,Simons M N,Maranas C D.SteadyCom:Predicting microbial abundances while ensuring community stability.PLoS Comput Biol,2017,13:e1005539
57 Mee M T,Collins J J,Church G M,et al.Syntrophic exchange in synthetic microbial communities.Proc Natl Acad Sci USA,2014,111:E2149-E2156
58 Johns N I,Blazejewski T,Gomes A L,et al.Principles for designing synthetic microbial communities.Curr Opin MicroBiol,2016,31:146-153
59 Sleight S C,Bartley B A,Lieviant J A,et al.Designing and engineering evolutionary robust genetic circuits.J Biol Eng,2010,4:12
60 Renda B A,Hammerling M J,Barrick J E.Engineering reduced evolutionary potential for synthetic biology.Mol BioSyst,2014,10:1668-1678
61 Villarreal F,Contreras-Llano L E,Chavez M,et al.Synthetic microbial consortia enable rapid assembly of pure translation machinery.Nat Chem Biol,2018,14:29-35
62 Grosskopf T,Soyer O S.Synthetic microbial communities.Curr Opin MicroBiol,2014,18:72-77
63 Peng X,Gilmore S P,O’Malley M A.Microbial communities for bioprocessing:Lessons learned from nature.Curr Opin Chem Eng,2016,14:103-109
64 Eng A,Borenstein E.An algorithm for designing minimal microbial communities with desired metabolic capacities.Bioinformatics,2016,32:2008-2016
65 Cortes-Tolalpa L,Salles J F,van Elsas J D.Bacterial synergism in lignocellulose biomass degradation-Complementary roles of degraders as influenced by complexity of the carbon source.Front Microbiol,2017,8:1628