cglI基因复合体在钝齿棒杆菌中的功能和行为研究
|
摘要
cglI基因复合体在钝齿棒杆菌中的功能和行为研究
目的
棒杆菌是工业生产氨基酸的重要菌种。由于发酵生产的规模化和连续性,生产中极易遭受噬菌体污染,严重影响企业生产过程,并给生产企业带来严重经济损失。生产中通常采用改进生产工艺,改善卫生条件,控制生产环节等措施预防噬菌体污染,虽然污染程度有所减轻,但仍时常发生。国内外一直采用菌株诱变的方法筛选抗噬菌体菌株,试图解决生产中的噬菌体污染问题。由于诱变获得的突变株存在生长缓慢,或其它生理性状改变,或生产能力下降,或只针对个别噬菌体有抗性,并易于产生回复突变等问题。所以,很难得到能用于生产的突变株。因此,噬菌体污染问题一直威胁着氨基酸的发酵生产。本文利用基因工程技术,在研究cglI基因复合体在大肠杆菌中克隆的有效方法基础上,通过将含有源自谷氨酸棒杆菌的限制修饰系统cglI基因复合体导入钝齿棒杆菌构建重组菌株,以探索cglI基因复合体用于构建抗噬菌体基因工程菌的可行性,以期从根本上解决氨基酸生产中的噬菌体污染问题。同时,对携带cglI基因复合体的重组质粒的稳定性及其对宿主细胞生长代谢的影响进行了研究。
方法
根据GenBank中cglI基因复合体的基因序列设计PCR引物,并于两端分别引入BamHI酶切位点序列。以谷氨酸棒杆菌CICC10226基因组DNA为模版,常规PCR扩增cglI基因片段,与克隆载体pMD18-T连接,构建重组克隆质粒pMD18-T-cglI。菌落PCR筛选转化子,测序分析克隆的基因片段的碱基组成。BamHI分别酶切重组克隆载体pMD18-T-cglI和棒杆菌穿梭表达载体pJL23,将回收的cglI基因片段和pJL23大片段用DNA连接酶连接,转化大肠杆菌HB101,筛选阳性克隆。制备重组质粒pJL23-cglI,酶切及PCR鉴定cglI基因片段大小和连接方向。大量制备重组质粒pJL23-cglI,电击转化到钝齿棒杆菌中,用含卡那霉素的LB平板筛选阳性克隆。酶切和PCR鉴定重组质粒后,噬菌体感染实验鉴定重组钝齿棒杆菌的功能活性。将构建的重组钝齿棒杆菌在无卡那霉素的LB平板上连续传100次,再从不同传代次数平板上分别挑取100个菌落,分别接种到有和无卡那霉素的LB平板上,测定重组质粒分离稳定性,将不同传代次数的菌落接种到无卡那霉素的LB液体培养基中,利用噬菌体感染实验测定重组质粒的结构稳定性。以野生钝齿棒杆菌做对照,通过测定生长曲线研究含cglI基因复合体的重组质粒对重组钝齿棒杆菌生长的影响;通过谷氨酸含量测定研究含cglI基因复合体重组质粒对重组钝齿棒杆菌代谢的影响。
结果
实验结果表明,以P1/P2为引物,PCR扩增得到了与预期大小一致(2177bp)的基因片段。克隆到载体pMD18-T后,经测序分析表明,克隆的基因片段与已知的cglI基因序列同源性达100%。cglI基因与棒杆菌穿梭表达载体pJL23重组构建的重组表达质粒pJL23-cglI,转化大肠杆菌HB101后,获得了阳性克隆菌株。经酶切和PCR鉴定证实了重组基因片段大小和正向连接方向。实验发现编码单独限制酶的基因在大肠杆菌HB101中表达了功能活性,但cglI基因复合体在大肠杆菌中未表达功能活性。重组表达质粒pJL23-cglI导入钝齿棒杆菌中后构建的重组钝齿棒杆菌经鉴定表明重组基因片段大小和连接方向未发生变化。功能活性研究表明,构建的重组钝齿棒杆菌对其相应的5种噬菌体显示了很强的限制活性,感染重组钝齿棒杆菌的噬菌体在胞内均未增殖。重组质粒pJL23-cglI在钝齿棒杆菌中的稳定性研究结果表明,重组钝齿棒杆菌连续传100代次后,重组质粒在钝齿棒杆菌中的分离稳定性和结构稳定性均达100%,表明重组质粒在钝齿棒杆菌中很稳定。生长曲线测定实验结果表明,与野生钝齿棒杆菌相比重组钝齿棒杆菌达到对数期的时间约延迟一小时左右,但达到稳定期的时间趋于相同。谷氨酸产生量实验结果表明,重组钝齿棒杆菌和野生钝齿棒杆菌在发酵过程中的谷氨酸积累量的变化趋势基本一致,显示了相同的谷氨酸产生高峰,32h的最大产生量分别为277.74mg/L和261.39mg/L,表明重组质粒pJL23-cglI的导入并未影响钝齿棒杆菌的代谢产酸量。
结论
本文以McrBC限制系统缺陷的大肠杆菌HB101作为宿主菌成功克隆了源自谷氨酸棒杆菌的限制修饰系统cglI基因复合体。将含有cglI基因复合体的重组质粒导入钝齿棒杆菌中,成功构建了抗噬菌体重组菌株,证实了cglI基因复合体在钝齿棒杆菌中的抗噬菌体功能活性。携带cglI基因复合体的重组质粒在钝齿棒杆菌中不但具有结构稳定性,而且具有很好的分离稳定性。重组质粒pJL23-cglI导入钝齿棒杆菌虽然对其早期生长有些影响,但并未影响其产生目的产物谷氨酸,进而证实了cglI基因复合体编码的甲基转移酶对宿主基因组DNA胞嘧啶甲基化基本不影响钝齿棒杆菌的生长代谢。本文利用cglI基因复合体构建抗噬菌体菌株,为从根本上解决氨基酸发酵生产中的噬菌体污染问题提供了一种有效方法,同时为cglI基因复合体的进一步应用奠定了理论基础。
Coryneform bacteria are important industrial producers of amino acid.The starter cultures are very susceptable to phage infection because of the large-scale and continuity of the fermentation process.As a result,the problem of phage infection has serious impact on the manufacture process and causes severe economic loss.Methods trditionally used to prevent phage infection in fermentation industry involve in ameliorating production technology and sanitation conditions,controlling manufacture links and so on.Though infection degree is alleviated,the problem still occasionally arises.Screening resistant mutants was usually adapted in order to solve the problem. The mutants often have the problems of lagged growth rate or other physiological character changes,low production capacity or narrow resistance range and reversible mutation.So it is not an easy thing to obtain fine mutation strains which are suitable for industrial manufacture.For the reasons above,the problem of phage infection has always been the threat to amino acid manufacture.In this paper,in order to explore the feasibility of applying cglI gene complex to construct engineered phage-resistant strains,and further,try to radically solve the phage infection in fermentation industry, cglI gene complex,the restriction-modification system from Corynebacterium glutamicum,was transformed into Corynebacterium crenatum to construct recombinant strain based on exploring the available approach of cloning cglI gene complex into E.coli.At the same time,the stability and influence of recombinant plasmid carrying cglI gene complex on the recombinant strain growth and metabolism were studied.
PCR primers were designed according to the sequence of cglI gene complex in GenBank,and the BamHI digestion site sequences were added to their 5' terminal. Using Corynebacterium glutamicum CICC10226 genome as template DNA,standard PCR amplified the cglI gene fragment.The recombinant plasmid pMD18-T-cglI was constructed by connecting the PCR products with cloning vector pMD18-T.The transformants were identified by colonial PCR,and the cglI gene fragment was sequenced.The recombinant cloning vector pMD18-T-cglI and coryneform bacteria shuttle vector pJL23 were both digested by BamHI.The recovered cglI gene fragment and pJL23 big fragment were connected by DNA ligase,and the products were transformed into E.coli HB 101.The recombinant plasmid was extracted,the size and ligation orientation of cglI gene fragment were identified by enzyme digestion and PCR amplification.The plasmid DNA of large-scale preparation was transformed into Corynebacterium crenatum by means of electrotransformation and the transformants were screened on LB plate with Km.After identified the recombinant plasmid by enzyme digestion and PCR amplification,the phage infection experiment was performed to identify the function activity of recombinant Corynebacterium crenatum. The recombinant Corynebacterium crenatum was continuously transferred 100 times on LB plate without Km.The plasmid segregation stability was measured by inoculating 100 colonies selected from each transferred time to LB plate with and without Km.The colonies of different transferred times were inoculated to LB liquid culture media without Km,and then phage infection experiment was carried out to measure the plasmid structure stability.The influence of the recombinant plasmid carrying cglI gene complex on the growth and metabolism of recombinant Corynebacterium crenatum was studied by measuring the growth carve and the glutamate production of recombinant strains,respectively.
Results
The result of cloning cglI gene complex indicated that the product of amplification by PCR using P1/P2 as primers was the same as had expected(2177bp).Sequence analysis showed the homology between the cloned gene fragment and the known gene sequence was 100%.Positive clones containing the recombinant expression vector pJL23-cg/I were obtained after cglI gene fragment and coryneform bacteria shuttle vector pJL23 were ligated and then transformed into E.coli HB 101.The gene size and ligation oritentaion are correct according to enzyme digestion and PCR amplification identification.It was found that the cglI restriction enzyme alone had the function activity in E.coli HB 101,but no activity was found for the whole cglI gene complex in E.coli HB101.The recombinant Corynebacterium crenatum was constructed by transforming recombinant expression plasmid pJL23-cg/I into Corynebacterium crenatum.No changes were observed in the gene size and ligation oritation according to the identification results.The research of function activity of cglI gene complex in Corynebacterium crenatum showed that the recombinant Corynebacterium crenatum had strong capacity of restriction activity to 5 kind of relative phages.It was indicated that the phages infecting the recombinant Corynebacterium crenatum failed to propagate inside the host cell.The stability research of recombinant plasmid revealed that the segregation and structural stabilities of recombinant plasmid in the Corynebacterium crenatum reached to 100%after 100 times of culture transferred continuously.The measure of growth rate demonstrated that,compared with wild Corynebacterium crenatum,the time of recombinant Corynebacterium crenatum reaching to logarithmic phase lagged about 1 h,but the time reaching to stationary phase tended to be identical.The measure of glutamate production manifested that recombinant Corynebacterium crenatum and wild Corynebacterium crenatum had the same tendency in glutamate accumulation.Both of them had the same top peak of glutamate accumulation at 32 h with 277.74mg/L and 261.39mg/L,respectively.This indicates that the introduction of recombinant plasmid pJL23-cg/I has no impact on the metabolism of Corynebacterium crenatum with respect to the acid production.
Using McrBC restriction system deficiency E.coli as host,the restriction-modification system cglI gene complex from Corynebacterium glutamicum was successfully cloned in this paper.Phage resistance strains were successfully constructed by transforming the recombinant plasmid carrying cglI gene complex into Corynebacterium crenatum.The function activity and broad resistance spectrum that cglI gene complex had in the Corynebacterium crenatum was confirmed.In the Corynebacterium crenatum,the recombinant plasmids carrying cglI gene complex were not only structural stability,but also segregation stability.Though the introduction of recombinant plasmid pJL23-cg/I into Corynebacterium crenatum had some impacts on the early growth of the recombinant strains,no impact was found on the production of glutamate.Thus,it was confirmed that cytosine methylation in the host genome which was methylated by the methyltransferases encoded by the cglI gene complex had no impact on the growth and metabolism of Corynebacterium crenatum.In this paper, an effective method was provided to radically solve the phage infection problem in fermentation industry.Also,theoretical foundation was established for further application of cglI gene complex.
目的
棒杆菌是工业生产氨基酸的重要菌种。由于发酵生产的规模化和连续性,生产中极易遭受噬菌体污染,严重影响企业生产过程,并给生产企业带来严重经济损失。生产中通常采用改进生产工艺,改善卫生条件,控制生产环节等措施预防噬菌体污染,虽然污染程度有所减轻,但仍时常发生。国内外一直采用菌株诱变的方法筛选抗噬菌体菌株,试图解决生产中的噬菌体污染问题。由于诱变获得的突变株存在生长缓慢,或其它生理性状改变,或生产能力下降,或只针对个别噬菌体有抗性,并易于产生回复突变等问题。所以,很难得到能用于生产的突变株。因此,噬菌体污染问题一直威胁着氨基酸的发酵生产。本文利用基因工程技术,在研究cglI基因复合体在大肠杆菌中克隆的有效方法基础上,通过将含有源自谷氨酸棒杆菌的限制修饰系统cglI基因复合体导入钝齿棒杆菌构建重组菌株,以探索cglI基因复合体用于构建抗噬菌体基因工程菌的可行性,以期从根本上解决氨基酸生产中的噬菌体污染问题。同时,对携带cglI基因复合体的重组质粒的稳定性及其对宿主细胞生长代谢的影响进行了研究。
方法
根据GenBank中cglI基因复合体的基因序列设计PCR引物,并于两端分别引入BamHI酶切位点序列。以谷氨酸棒杆菌CICC10226基因组DNA为模版,常规PCR扩增cglI基因片段,与克隆载体pMD18-T连接,构建重组克隆质粒pMD18-T-cglI。菌落PCR筛选转化子,测序分析克隆的基因片段的碱基组成。BamHI分别酶切重组克隆载体pMD18-T-cglI和棒杆菌穿梭表达载体pJL23,将回收的cglI基因片段和pJL23大片段用DNA连接酶连接,转化大肠杆菌HB101,筛选阳性克隆。制备重组质粒pJL23-cglI,酶切及PCR鉴定cglI基因片段大小和连接方向。大量制备重组质粒pJL23-cglI,电击转化到钝齿棒杆菌中,用含卡那霉素的LB平板筛选阳性克隆。酶切和PCR鉴定重组质粒后,噬菌体感染实验鉴定重组钝齿棒杆菌的功能活性。将构建的重组钝齿棒杆菌在无卡那霉素的LB平板上连续传100次,再从不同传代次数平板上分别挑取100个菌落,分别接种到有和无卡那霉素的LB平板上,测定重组质粒分离稳定性,将不同传代次数的菌落接种到无卡那霉素的LB液体培养基中,利用噬菌体感染实验测定重组质粒的结构稳定性。以野生钝齿棒杆菌做对照,通过测定生长曲线研究含cglI基因复合体的重组质粒对重组钝齿棒杆菌生长的影响;通过谷氨酸含量测定研究含cglI基因复合体重组质粒对重组钝齿棒杆菌代谢的影响。
结果
实验结果表明,以P1/P2为引物,PCR扩增得到了与预期大小一致(2177bp)的基因片段。克隆到载体pMD18-T后,经测序分析表明,克隆的基因片段与已知的cglI基因序列同源性达100%。cglI基因与棒杆菌穿梭表达载体pJL23重组构建的重组表达质粒pJL23-cglI,转化大肠杆菌HB101后,获得了阳性克隆菌株。经酶切和PCR鉴定证实了重组基因片段大小和正向连接方向。实验发现编码单独限制酶的基因在大肠杆菌HB101中表达了功能活性,但cglI基因复合体在大肠杆菌中未表达功能活性。重组表达质粒pJL23-cglI导入钝齿棒杆菌中后构建的重组钝齿棒杆菌经鉴定表明重组基因片段大小和连接方向未发生变化。功能活性研究表明,构建的重组钝齿棒杆菌对其相应的5种噬菌体显示了很强的限制活性,感染重组钝齿棒杆菌的噬菌体在胞内均未增殖。重组质粒pJL23-cglI在钝齿棒杆菌中的稳定性研究结果表明,重组钝齿棒杆菌连续传100代次后,重组质粒在钝齿棒杆菌中的分离稳定性和结构稳定性均达100%,表明重组质粒在钝齿棒杆菌中很稳定。生长曲线测定实验结果表明,与野生钝齿棒杆菌相比重组钝齿棒杆菌达到对数期的时间约延迟一小时左右,但达到稳定期的时间趋于相同。谷氨酸产生量实验结果表明,重组钝齿棒杆菌和野生钝齿棒杆菌在发酵过程中的谷氨酸积累量的变化趋势基本一致,显示了相同的谷氨酸产生高峰,32h的最大产生量分别为277.74mg/L和261.39mg/L,表明重组质粒pJL23-cglI的导入并未影响钝齿棒杆菌的代谢产酸量。
结论
本文以McrBC限制系统缺陷的大肠杆菌HB101作为宿主菌成功克隆了源自谷氨酸棒杆菌的限制修饰系统cglI基因复合体。将含有cglI基因复合体的重组质粒导入钝齿棒杆菌中,成功构建了抗噬菌体重组菌株,证实了cglI基因复合体在钝齿棒杆菌中的抗噬菌体功能活性。携带cglI基因复合体的重组质粒在钝齿棒杆菌中不但具有结构稳定性,而且具有很好的分离稳定性。重组质粒pJL23-cglI导入钝齿棒杆菌虽然对其早期生长有些影响,但并未影响其产生目的产物谷氨酸,进而证实了cglI基因复合体编码的甲基转移酶对宿主基因组DNA胞嘧啶甲基化基本不影响钝齿棒杆菌的生长代谢。本文利用cglI基因复合体构建抗噬菌体菌株,为从根本上解决氨基酸发酵生产中的噬菌体污染问题提供了一种有效方法,同时为cglI基因复合体的进一步应用奠定了理论基础。
Coryneform bacteria are important industrial producers of amino acid.The starter cultures are very susceptable to phage infection because of the large-scale and continuity of the fermentation process.As a result,the problem of phage infection has serious impact on the manufacture process and causes severe economic loss.Methods trditionally used to prevent phage infection in fermentation industry involve in ameliorating production technology and sanitation conditions,controlling manufacture links and so on.Though infection degree is alleviated,the problem still occasionally arises.Screening resistant mutants was usually adapted in order to solve the problem. The mutants often have the problems of lagged growth rate or other physiological character changes,low production capacity or narrow resistance range and reversible mutation.So it is not an easy thing to obtain fine mutation strains which are suitable for industrial manufacture.For the reasons above,the problem of phage infection has always been the threat to amino acid manufacture.In this paper,in order to explore the feasibility of applying cglI gene complex to construct engineered phage-resistant strains,and further,try to radically solve the phage infection in fermentation industry, cglI gene complex,the restriction-modification system from Corynebacterium glutamicum,was transformed into Corynebacterium crenatum to construct recombinant strain based on exploring the available approach of cloning cglI gene complex into E.coli.At the same time,the stability and influence of recombinant plasmid carrying cglI gene complex on the recombinant strain growth and metabolism were studied.
PCR primers were designed according to the sequence of cglI gene complex in GenBank,and the BamHI digestion site sequences were added to their 5' terminal. Using Corynebacterium glutamicum CICC10226 genome as template DNA,standard PCR amplified the cglI gene fragment.The recombinant plasmid pMD18-T-cglI was constructed by connecting the PCR products with cloning vector pMD18-T.The transformants were identified by colonial PCR,and the cglI gene fragment was sequenced.The recombinant cloning vector pMD18-T-cglI and coryneform bacteria shuttle vector pJL23 were both digested by BamHI.The recovered cglI gene fragment and pJL23 big fragment were connected by DNA ligase,and the products were transformed into E.coli HB 101.The recombinant plasmid was extracted,the size and ligation orientation of cglI gene fragment were identified by enzyme digestion and PCR amplification.The plasmid DNA of large-scale preparation was transformed into Corynebacterium crenatum by means of electrotransformation and the transformants were screened on LB plate with Km.After identified the recombinant plasmid by enzyme digestion and PCR amplification,the phage infection experiment was performed to identify the function activity of recombinant Corynebacterium crenatum. The recombinant Corynebacterium crenatum was continuously transferred 100 times on LB plate without Km.The plasmid segregation stability was measured by inoculating 100 colonies selected from each transferred time to LB plate with and without Km.The colonies of different transferred times were inoculated to LB liquid culture media without Km,and then phage infection experiment was carried out to measure the plasmid structure stability.The influence of the recombinant plasmid carrying cglI gene complex on the growth and metabolism of recombinant Corynebacterium crenatum was studied by measuring the growth carve and the glutamate production of recombinant strains,respectively.
Results
The result of cloning cglI gene complex indicated that the product of amplification by PCR using P1/P2 as primers was the same as had expected(2177bp).Sequence analysis showed the homology between the cloned gene fragment and the known gene sequence was 100%.Positive clones containing the recombinant expression vector pJL23-cg/I were obtained after cglI gene fragment and coryneform bacteria shuttle vector pJL23 were ligated and then transformed into E.coli HB 101.The gene size and ligation oritentaion are correct according to enzyme digestion and PCR amplification identification.It was found that the cglI restriction enzyme alone had the function activity in E.coli HB 101,but no activity was found for the whole cglI gene complex in E.coli HB101.The recombinant Corynebacterium crenatum was constructed by transforming recombinant expression plasmid pJL23-cg/I into Corynebacterium crenatum.No changes were observed in the gene size and ligation oritation according to the identification results.The research of function activity of cglI gene complex in Corynebacterium crenatum showed that the recombinant Corynebacterium crenatum had strong capacity of restriction activity to 5 kind of relative phages.It was indicated that the phages infecting the recombinant Corynebacterium crenatum failed to propagate inside the host cell.The stability research of recombinant plasmid revealed that the segregation and structural stabilities of recombinant plasmid in the Corynebacterium crenatum reached to 100%after 100 times of culture transferred continuously.The measure of growth rate demonstrated that,compared with wild Corynebacterium crenatum,the time of recombinant Corynebacterium crenatum reaching to logarithmic phase lagged about 1 h,but the time reaching to stationary phase tended to be identical.The measure of glutamate production manifested that recombinant Corynebacterium crenatum and wild Corynebacterium crenatum had the same tendency in glutamate accumulation.Both of them had the same top peak of glutamate accumulation at 32 h with 277.74mg/L and 261.39mg/L,respectively.This indicates that the introduction of recombinant plasmid pJL23-cg/I has no impact on the metabolism of Corynebacterium crenatum with respect to the acid production.
Using McrBC restriction system deficiency E.coli as host,the restriction-modification system cglI gene complex from Corynebacterium glutamicum was successfully cloned in this paper.Phage resistance strains were successfully constructed by transforming the recombinant plasmid carrying cglI gene complex into Corynebacterium crenatum.The function activity and broad resistance spectrum that cglI gene complex had in the Corynebacterium crenatum was confirmed.In the Corynebacterium crenatum,the recombinant plasmids carrying cglI gene complex were not only structural stability,but also segregation stability.Though the introduction of recombinant plasmid pJL23-cg/I into Corynebacterium crenatum had some impacts on the early growth of the recombinant strains,no impact was found on the production of glutamate.Thus,it was confirmed that cytosine methylation in the host genome which was methylated by the methyltransferases encoded by the cglI gene complex had no impact on the growth and metabolism of Corynebacterium crenatum.In this paper, an effective method was provided to radically solve the phage infection problem in fermentation industry.Also,theoretical foundation was established for further application of cglI gene complex.
引文
1 Hermann T.Industrial production of amino acids by coryneform bateria[J].J Biotech.2003;104(10);155-172.
2 彭珍荣.微生物资源与氨基酸的生产和应用[J].化学与生物工程.2003;20(6);7-9.
3 袁品坦.再谈噬菌体的污染及其预防[J].发酵科技通讯.1999;28(4);22-27.
4 沈锡辉,刘双江.谷氨酸棒杆菌中芳香化合物降解的β-酮己二酸途径中原儿茶酸分支关键酶的鉴定[J].中国科学(C辑).2004;34(6);547-554.
5 何宁,李寅,陈坚,等.谷氨酸棒杆菌合成新型生物絮凝剂分批发酵过程的溶氧控制模式[J].环境科学学报.2004;24(3);492-497.
6 Salim K,Haedens V,Content J,et al.Heterolgous expression of the Mycobacterium tuberculosis gene encoding antigen 85A in Corynebacterium glutamicum[J].Appl Environ Microbiol.1997;63(11);4392-4400.
7 Puech V,Bayan N,Salim K,et al.Characterization of the in vivo acceptors of the mycolyl residues transferred by the corynebacterial PS1 and the related mycobacterial antigen 85[J].MolMicrobiol.2000;35(5);1026-1041.
8 Sander M E.Bateriophages in industrial fermentations.In;Webster R G.Granoff A(Eds).Encyclopedia of Virology[M].Lodon;Academic Press,1993.p.117-121.
9 袁品坦.谷氨酸菌种选育的进展及其回顾[J].发酵科技通讯.2000;39(1);15-20.
10 杨汝德,张玉榽,陈连就.抗噬菌体突变株U-9的选育[J].发酵科技通讯.1986;(2);49-54.
11 单志萍,吴燕,陆茂林,等.谷氨酸产生菌T6-13抗噬菌体突变株的选育[J].发酵科技通讯.1990;(2);19-23.
12 武标,张千,赫英军,等.抗噬菌体谷氨酸高产菌株选育[J].激光生物学报.2006,15(4);399-412
13 Schafer A,Schwarzer A,Kalinowski J,et al.Cloning and characterization of a DNA region encoding a stress-sensitive restriction system from Corynebacterium glutamicum ATCC 13032 and analysis of its role in intergeneric conjugation with Escherichia coli[J].J Bacteriol. 1994;176(23);7309-7319.
14 Schafer A,Tauch A,Droste N,et al.The Corynebacterium glutamicum cgllM gene encoding a 5-cytosine methyltransferase enzyme confers a specific DNA methylation pattern in an McrBC-deficient Escherichia coli strain[J].Gene.1997;203(2);95-101.
15 陆军,唐炯,张文波,等.棒状杆菌表达载体pJL23的构建[J].复旦学报(自然科学版).2000;39(3);292-296.
16 Sambrook J,Rusell D W.Molecular cloning;A laboratory Manual,3rd Ed[M].In;Cold Spring Harbor.New York;Cold Spring Harbor Laboratory Press,2001.
17 余茂效,司穉东.噬菌体实验技术[M].北京;科学出版社,1991.p.11-12.
18 Kong J,Josephsen J.The ability of the plasmid-encoded restriction and modification system LlaBⅢ to protect Lactococcus lactis against bacteriophages[J].Lett Appl Microbiol.2002;34(4);249-253.
19 Kobayashi I.Behavior of restriction-modification systems as selfish mobile elements and their impact on genome evolution[J].Nucleic Acids Research.2001;29(18);3742-3756.
20 Roberts R J.Restriction and modification enzymes and their recognition sequences[J].Gene.1978;4;183-193.
21 Roberts R J,Vincze T,Posfal J,et al.REBASE - restriction enzymes and DNA methyltransferases[J].Nucleic Acids Research.2005;33(Database Issue);230-232.
22 Pingoud A,Fuxreiter M,Pingoud V,et al.Type II restriction endonucleases;structure and mechanism[J].Cell Mol Life Sci.2005;62(6);685-707.
23 Roberts R J,Belfort M,Bestor T,et al.A nomenclature for restriction enzymes,DNA methyltransferases,homing endonucleases and their genes[J].Nucleic Acid Res.2003;31(7);805-1812.
24 Lin L F,Posfai J,Robert R J,et al.Comparative genomics of therestriction -modification systems in Helicobacterpylori[J].Proc Natl Acad Sci USA.2001;98(5);2740-2745.
25 Izsvak Z,Jobbagy Z,Takacs I,et al.Cloning and characterization of the gene of the ceqI restriction-modification system[J].J Biochem Cell Biol.1997;29(6);895-900.
26 Mann M B,Rao R N,Smith H O.Cloning of restriction and modification genes in E.coli;the Hba II system from Haemophilus haemolyticus[J]. Gene. 1978; 3(2): 97-112.
27 Xu S Y, Xiao J P, Ettwiller L, et al. Cloning and expression of the ApaLI, NspI, NspHI, SacI, ScaI, and SapI restriction-modification systems in Escherichia coli[J]. Mol Gen Genet. 1998; 260(2-3): 226-231.
28 Meselson M, Yuan R. DNA restriction enzyme from E. coli[J]. Nature. 1968; 3(23): 1110 -1114.
29 Zhu Z Y, Robinson D, Benne J, et al. Method for cloning and expression of Tth111 II restriction endonuclease-methylase in E. coli[P]. USA, Invent. Patent, No. 6919194. 2004.
30 Howard K A, Card C, Benner J S, et al. Cloning the Ddel restriction-modification system using a two-step method[J]. Nucleic Aci Res. 1986; 14(20): 7939-7951.
31 Brooks J E, Benner J S, Silber K R, et al. Cloning and characterization of the BamHI restriction modification system[J]. Gene. 1988; 74(1): 13.
32 Zhu Z Y, Xu S Y. Method for cloning and expression of BsaI restriction endonuclease and BsaI methylase in E. coli[?]. USA, Invent. Patent, No.6723546. 2004.
33 Xu S Y, Maunus R, Stropnicky K. Method for cloning and expression of MspAll restriction endonuclease and MspAll methylase in E.coli[P]. USA, Invent. Patent, No.6673588. 2004.
34 Elisabeth A, Raleigh, Wilson G. Escherichia coli K-12 Restricts DNA Containing 5-methylcytosine[J]. PNAS. 1986; 83(23): 9070-9074.
35 Heitman J, Model P. Site-specific methylases induce the SOS DNA repair response in Escherichia coli[i]. J Bacteriol. 1987; 69(7): 3243-3250.
36 Raleigh E A. Organization and function of the mcrBC genes of Escherichia coli K-12 [J]. Mol Microbiol. 1992; 6(9): 1079-1086.
37 Tauch A, Homann I, Mormann S, et al. Strategy to sequence the genome of Corynebacterium glutamicum ATCC 13032: use of a cosmid and a bacterial artificial chromosome library[J]. J Biotechnol. 2002; 95(1): 25-38.
38 Nakayama Y, Kobayashi I. Restriction-modification gene complexes as selfish gene entities: Roles of a regulatory system in their establishment, maintenance, and apoptotic mutual exclusion[J]. Proc Nat Acad Sci USA. 1998; 95(11): 6442-6447.
39 Kobayashi I.DNA modification and restriction;Selfish behavior of an epigenetic system.In;Russo V,Martienssen R,Riggs A(eds.).Epigenetic mechanisms of gene regulation[M].New York;Cold Spring Harbor Laboratory Press,1996.p.155-172.
40 Knowle D,Lintner R E,Touma Y M,et al.Nature of the Promoter Activated by C.Pvu II,an Unusual Regulatory Protein Conserved among Restriction-Modification Systems[J].J Bacteriol.2005;187(2);488-497.
41 Kobayashi I.Restriction-modification systems as minimal forms of life.In;Pingoud A.(ed.),Restriction endonucleases[M].Berlin,Germany;Springer-Verlag,2004.p;19-62.
42 Murray N E.Immigration control of DNA in bacteria;Self versus non-self[J].Microbiology.2002;148(1);3-20.
43 McGeehan J E,Papapanagiotou I,Streeter S D,et al.Cooperative binding of the C.AhdI controller protein to the C/R promoter and its role in endonuclease gene expression[J].Mol Biol.2006;358(1);523-531.
44 王家驯,朱素娟,戈宝榛,等.谷氨酸生产菌株T6-13噬菌体的分离及其血清型分布[J].工业微生物.1990;20(4);6-9.
45 袁品坦.谷氨酸发酵中噬菌体污染的防治[J].发酵科技通讯.1992;2(1);46-52.
46 邱炜炜,林有波,谢天阳.预防噬菌体污染的有效方法[J].发酵科技通讯.2000;29(1);38-39.
47 Coffey A,Ross R P.Bacteriophage-resistance systems in dairy starter strains;molecular analysis to application[J].Antonie van Leeuwenhoek.2002;82(1-4);303-321.
48 Forde A,Fitzgerald G F.Bacteriophage defense systems in lactic acid bacteria[J].Antonie van Leeuwenhoek.1999;76(1-4);89-113.
49 Lucchini S,Sidoti J,Brussow H.Broad-range bacteriophage resistance in Streptococcus thermophilus by insertional mutagenesis[J].Virology.2000;275(2);267-272.
50 余秉琦,沈微,诸葛健.适用于异源DNA高效整合转化的谷氨酸棒杆菌电转化法[J].中国生物工程杂志.2005;25(2);78-81.
51 Klaenhammer T R.Genetic characterization of multiple mechanisms of phage defense from a prototype phage-insensitive strain Lactococeus laetis ME2[J].J Dairy Sci.1989;72; 3429-3443.
52 Klaenhammer T R,Romero D,Sing W,et al.Molecular analysis of pTR2030 gene systems that confer phage resistance to lactococci.In;Dunny G,Cleary P,McKay L(eds.).Genetics and Molecular Biology of Streptococci,Lactococci,and Enterococci[M].Washington,DC;American Society for Microbiology Press,1991.p.124-130.
53 Duckworth D H,Glenn J,McCorquodale D J.Inhibition of bacteriophage replication by extra-chromosomal elements[J].Microbiol Rev.1981;45(1);52-71.
54 McGrath S,Seegers J F M L,Fitzgerald G F,et al.Molecular Characterization of a Phage-Encoded Resistance System in Lactococcus lactis[J].Appl Environ Microbiol.1999;65(5);1891-1899.
55 Sturino J M,Klaenhammer T R.Engineeried Bacteriophage- defence systems in bioprocessing[J].Microbiology.2006;4(10);395-404.
56 Moineau S,Emond E,Walker S A,et al.DNA encoding phage resistance protein[P].USA,Invent.Patent,No.5994118.1999.
57 Mollet B,Pridmore D,Zwahlen M C.Phage-resistant streptococcus[P].USA,Invent.Patent,No.5766904.1998.
58 Moineau S,Walker S A,Vedamuthu E R,et al.Enzyme for phage resistance[P].USA,Invent.Patent,No.5972673.1999.
59 韦平和,吴梧桐.色氨酸生物工程研究进展[J].药物生物技术.1998;5(3);180-185.
60 Cases I,Lorenzo V D.Genetically modified organisms for the environment;Stories of success and failure and what we have learned from them[J].Int Microbiol.2005;8(3);213-222.
61 喻国策,焦瑞身,王骥程等.大肠杆菌HBl01(pBR322)高密度培养过程质粒的稳定性[J].过程工程学报.2001;1(2);185-189.
62 Friehs K.Plasmid copy number ahd plasmid stability[J].Adv Biochem Eng Biotechnol.2004;86(10);47-82.
63 Friehs K,Reardon K F.Parameters influencing the productivity of recombinant E.coli cultivations[J].Adv Biochem Eng Biotechnol.1993;48(10);53-77.
64 Gerdes K, Jacobsen J S, Franch T. Plasmid stabilization by post -segregational killing[J]. Genet Eng. 1997; 19(1): 49-61.
65 Kobayashi I. Genetic addiction: a principle in symbiosis of genes in a genome, In Funnel B E, Phillips G J (eds.). Plasmid biology[M]. Washington, D.C: ASM Press, 2004. p. 105-144.
66 Koyama A H, Wada C, Nagata T, et al. Indirect selection for plasmid mutants: Isolation of ColVBtrp mutants defective in self-maintenance in Escherichia coli[J]. J Bacteriol. 1975; 122(1): 73-79.
67 Gerdes K. Toxin-antitoxin modules may regulate synthesis of macromolecules during nutritional stress[J]. J Bacteriol. 2000; 182(3): 561-572.
68 Gerdes K, Gultyaev A P, Franch T, et al. Antisense RNA-regulated programmed cell death[J]. Annu Rev Genet. 1997; 31(10): 1-31.
69 Zielenkiewicz U, Ceglowski P. Mechanisms of plasmid stable maintenance with special focuson plasmid addiction system[J]. Acta Biochimica Polonica. 2001; 48(4): 1003-1023.
70 Naito T, Kusano K, Kobayashi I. Selfish behavior of restriction-modification systems [J]. Science. 1995; 267(5199): 897-899.
71 Kulakauskas S, Lubys A, Ehrlich S D. DNA restriction- modification systems mediate plasmid maintenance[J]. J Bacteriol. 1995; 177(12): 3451-3454.
72 Kusano K, Naito T, Handa N, et al. Restriction-modification systems as genomic parasites in competition for specific sequences[J]. Proc Natl Acad Sci USA. 1995; 92(24): 11095-11099.
73 Handa N, Kobayashi I. Post-segregational killing by restriction modification gene complexes: observations of individual cell deaths[J]. Biochimie. 1999; 81(8-9): 931-938.
74 Handa N, Ichige A, Kusano K, et al. Cellular responses to postsegregational killing by restriction-modification genes[J]. J Bacteriol. 2000; 182(8): 2218-2229.
75 Chinen A, Naito Y, Handa N, et al. Evolution of sequence recognition by restriction-modification enzymes: selective pressure for specificity decrease[J]. Mol Biol Evol.2000; 17(11): 1610-1619.
76 Takahashi N, Naito Y, Handa N, et al. A DNA methyltransferase can protect the genome from postdisturbance attack by a restriction-modification gene complex[J]. J Bacteriol. 2002; 184(22);6100-6108.
77 Patnaik P R.An evaluation of models for the effect of plasmid copy number on bacterial growth rate[J].Biotechnol Lett.2000;22(21);1719-1725.
78 天津轻工业学院,大连轻工业学院,无锡轻工大学,等.工业发酵分析[M].北京;中国轻工业出版社,2004.p.99-108.
79 葛保胜,任育红,唐志红,等.表达重组别藻蓝蛋白质粒在工程菌株中的遗传稳定性研究[J].微生物学通报.2005;32(4);37-41.
80 沈萍,范秀容,李广武.微生物学实验(第三版)[M].北京;高等教育出版社,1999.D.141-143.
81 Ricci J C D,Hemandez M E.Plasmid effects on Escherichia coli metabolism[J].Crit Rev Biotechnol.2000;20(2);79-108.
82 Lee K,Moon S H.Growth kinetics of Lactococcus lactis ssp.diacetylactis harboring different plasmid content[J].Curr Microbiol.2003;47(1);17-21.
83 崔卫国,聂风强.提高谷氨酸发酵产酸水平的研究[J].发酵科技通讯.2001;30(2);1-2.
84 Casadesus J,Low D.Epigenetic gene regulation in the bacterial world[J].Microbiol Mol Biol Rev.2006;70(3);830-856.
1 Twort F.An investigation on the nature of ultramicroscopic viruses[J].Lancet.1915;2;1241-1243.
2 D'Herelle F.Sur un microbe invisible antagoniste des bacilles dysenteriques[J].Comp Rend Acad Sci.1917;165;373-375.
3 Maniloff J,Cadden S P,Putzrath R M.Maturation of an enveloped budding phage;Mycoplasmavirus L2[J].Prog Clin Biol Res.1981;64;503-513.
4 Sable S,Lortal S.The lysins of bacteriophages infecting lactic acid bacteria[J].Appl Microbiol Biotechnol.1995;43(11);1-6.
5 Wang I N,Smith D L,Young R.Holins;The protein clocks of bacteriophage infections[J].Annu Rev Microbiol.2000;54(1);799-825.
6 Madera C,Monjardin C,Suarez J E.Milk contamination and resistance to processing conditions determine the fate of Lactococcus lactis bacteriophages in dairies[J].Appl Environ Microbiol.2004;70(12);7365-7371.
7 袁品垣.再谈噬菌体的污染及其预防[J].发酵科技通讯.1999;28(4);22-27.
8 修文琼,列书锋,何爱华,等.福建各地抗生素厂生产菌株污染噬菌体的电镜监测[J].海峡预防医学杂志.2000;6(6);41-42.
9 李英朝,李艳,贾宁,等.维生素B12生产中噬菌体污染的检查与预防[J].河北工业科技.2000;17(4);42-48.
10 赵峰梅,孙文敬,米丽娟,等.噬菌体污染对荧光假单胞菌K1005 2-酮基-D-葡萄糖酸发酵的影响[J].食品科学.2002;23(6);72-74.
11 Huggins A R,Sandine W E.Selection and charaterization of phage insensitive Lactic streptococci[J].J Dairy Sci.1979;62;70-71.
12 Klaenhammer T R.Interaction of bacteriophage with Lactic streptococci[J].Adv Appl Microbiol.1984;30(1);1-29.
13 Sandine W E.Use of bacteriophage-resistant mutants of lactococcal starters in cheese-making[J]. Neth Milk Dairy J. 1989; 43:211 -219.
14 Bester B H, Lombard S H. Protection of starter cultures against bacteriophages by propagation in a phage-resistant medium[J]. South African J Dairy Technol. 1975; 7: 235-450.
15 Gulstrom T J, Pearce L E, Sandine W E, et al. Evaluation of commercial phage inhibitory media[J]. J Dairy Sci. 1979; 62: 208-221.
16 Daly C. The use of mesophilic cultures in the dairy industry[J]. Antonie Van Leeuwenhoek. 1983; 49(3): 297-312.
17 Lowrie R J, Pearce L E. The plating efficiency of bacteriophages of Lactic streptococci[J]. N Z J Dairy Sci Technol. 1971; 6: 166-171.
18 Lubbers M W, Waterfield N R, Beresford T P, et al. Sequencing and analysis of the prolate-headed lactococcal bacteriophage c2 genome and identification of the structural genes[J]. Appl Environ Microbiol. 1995; 61(12): 4348-4356.
19 Coffey A, Ross R P, Bacteriophage-resistance systems in dairy starter strains: molecular analysis to application[J]. Antonie Van Leeuwenhoek. 2002; 82(1-4): 303-321.
20 Forde A, Fitzgerald G F. Bacteriophage defense systems in lactic acid bacteria[J]. Antonie Van Leeuwenhoek. 1999; 76(1-4): 89-113.
21 Lucchini S, Sidoti J, Bru ssow H. Broad-range bacteriophage resistance in Streptococcus thermophilus by insertional mutagenesis[J]. Virology. 2000; 275(2): 267-272.
22 Budde-Niekiel A, Teuber M. Electron microscopy of the adsorption of bacteriophages to lactic acid streptococci[J]. Milchwissenschaft. 1987; 42: 551-553.
23 Quiberoni A, Stiefel L I, Reinheimer J A . Characterization of phage receptors in Streptococcus thermophilus using purified cell walls obtained by a simple protocol[J]. J Appl Microbiol. 2000; 89(6): 1059-1065.
24 Klaenhammer T R, Fitzgerald G F. Bacteriophage and bacteriophage resistance. In : Gasson M J, de Vos W M (eds.). Genetics and Biotechnology of Lactic Acid Bacteria [M]. London: Chapman and Hall, 1994. p. 106-168.
25 Broadbent J R, McMahon D J, Welker D L, et al. Biochemistry, genetics, and applications of exopolysaccharide production in Streptococcus thermophilus: A review[J]. J Dairy Sci. 2003; 86(2): 407-423.
26 Klaenhammer T R. Genetic characterization of multiple mechanisms of phage defense from a prototype phage-insensitive strain Lactococcus lactis ME2[J]. J Dairy Sci. 1989; 72: 3429-3443.
27 Klaenhammer T R, Romero D, Sing W, et al. Molecular analysis of pTR2030 gene systems that confer phage resistance to lactococci. In: Dunny G, Cleary P, and McKay L(eds.). Genetics and Molecular Biology of Streptococci, Lactococci, and Enterococci[M]. Washington, DC : American Society for Microbiology Press, 1991. p. 124-130.
28 Roberts R J, Belfort M, Bestor T, et al. A nomenclature for restriction enzymes, DNA methyltransferases, homing endonucleases and their genes[J]. Nucleic Acids Res. 2003; 31(7): 1805-1812.
29 Moineau S, Pandian S, Klaenhammer T R. Restriction/ modification systems and restriction endonucleases are more effective on lactococcal bacteriophages that have emerged recently in the dairy industry[J]. Appl Environ Microbiol. 1993; 59(1):197-202.
30 Powell I A, Davidson B E. Resistance to in vitro restriction of DNA from Lactic streptococcal bacteriophage c6A[J]. Appl Environ Microbiol. 1986; 51:1358-1360.
31 Wilson G G, Murray N E. Restriction and modification systems[J]. Annu Rev Genet. 1991; 25(10): 585-627.
32 Bickle T A, Kruger D H. Biology of DNA restriction[J]. Microbiol Rev. 1993; 57(2): 434-450.
33 Hill C, Miller L A, Klaenhammer T R. In vivo genetic exchange of a functional domain from a type IIA methylase between lactococcal plasmid pTR2030 and a virulent bacteriophage[J]. J Bacteriol. 1991; 173(14): 4363-4370.
34 Klaenhammer T R, Sanozky R. Conjugal transfer from Streptococcus lactis ME2 of plasmids encoding phage resistance, nisin resistance and lactosefermenting ability: Evidence for a high-frequency conjugative plasmid responsible for abortive infection of virulent bacteriophage[J]. J Gen Microbiol. 1985; 131(2): 1531-1541.
35 Sing W D, Klaenhammer T R. A strategy for rotation of different bacteriophage defenses in a lactococcal single-strain starter culture system[J]. Appl Environ Microbiol. 1993; 59(2): 365-372.
36 Durmaz E, Klaenhammer T R. A starter culture rotation strategy incorporating paired restriction/modification and abortive infection bacteriphage defenses in a single Lactococcus lactis strain[J]. Appl Environ Microbiol. 1995; 61(4): 1266-1273.
37 Burrus V, Bontemps C, Decaris B, et al. Characterization of a novel type II restriction-modification system, Sth368I, encoded by the integrative element ICEStl of Streptococcus thermophilus CNRZ368[J]. Appl Environ Microbiol. 2001; 67(4): 1522-1528.
38 Poch M T, Somkuti G A , Solaiman D K Y. Sthl32I, a novel class-IIS restriction endonuclease of Streptococcus thermophilus ST132[J]. Gene. 1997; 195(2): 201-206.
39 Duckworth D H, Glenn J, McCorquodale D J. Inhibition of bacteriophage replication by extra-chromosomal elements[J]. Microbiol Rev. 1981; 45: 52-71.
40 Allison G E , Klaenhammer T R. Phage resistance mechanisms in lactic acid bacteria[J]. Int Dairy J. 1998; 8(3): 207-226.
41 Casey J, Daly C, Fitzerald G F. Controlled integration into the Lactococcus chromosome of the pCI829-encoded abortive infection gene from Lactococcus lactis subsp.lactis UC811[J]. Appl Environ Microbiol. 1992; 58(10): 3283-3291.
42 Dinsmore P K, Klaenhammer T R. Phenotypic consequences of altering the copy number of abiA, a gene responsible for aborting bacteriophage infections in Lactococcus lactis[J]. Appl Environ Microbiol. 1994; 60(4): 1129-1136.
43 Garvey P, van Sinderen D, Twomey D P, et al. Molecular genetics of bacteriophage and natural phage defense systems in the genus Lactococcus[J]. Int Dairy J. 1995; 5(1): 905-947.
44 Sanders M E, Klaenhammer T R. Characterization of phage-sensitive mutants from a phage-insensitive strain of Streptococcus lactis: evidence for a plasmid determinant that prevents phage adsorption[J]. Appl Environ Microbiol. 1983; 46: 1125-1133.
45 Chopin A, Chopin M C, Moillo-Batt A, et al. Two plasmid- determined restriction and modification systems in Streptococcus lactis[J] . Plasmid. 1984; 11: 260-263.
46 Froseth B R, Harlander S K and McKay L L. Plasmid-mediated reduced phage sensitivity in Streptococcus lactis KR5[J]. J Dairy Sci. 1988; 71: 275-284.
47 Durmaz E, Higgins D L, Klaenhammer T R. Molecular characterization of a second abortive phage resistance gene present in Lactococcus lactis subsp.lactis ME2[J]. J Bacteriol. 1992; 174(22): 7463-7469.
48 Higgins D L, Sanozky-Dawes R B, Klaenhammer T R. Restriction and modification activities from Streptococcus lactis ME2 are encoded by a self-transmissible plasmid, pTN20, that forms cointegrates during mobilization of lactose-fermenting-ability[J]. J Bacteriol. 1988; 170(8): 3435-3442.
49 Hill C, Massey I J, Klaenhammer T R. Rapid method to characterize lactococcal bacteriophage genomes[J]. Appl Environ Microbiol. 1991; 57(1): 283-288.
50 Coleman J, Hirashima A, Inokuchi Y, et al. A novel immune system against bacteriophage infection using complementary RNA(micRNA) [J]. Nature. 1985; 315(6020): 601-603.
51 Kim S G, Batt C A. Antisense mRNA-mediated bacteriophage-resistance in Lactococcus lactis ssp.lactis[J]. Appl Environ Microbiol. 1991; 57(4): 1109-1113.
52 Chung D K, Kim J H, Batt C A. Cloning and nucleotide sequence of the major capsid protein from Lactococcus lactis ssp.cremoris bacteiophage F4-1[J]. Gene. 1991; 101(1): 121-125.
53 Chung D K, Chung S K, Batt C A. Antisense RNA directed against the major capsid protein from Lactococcus lactis ssp.cremoris bacteriophage F4-1 confers partial resistance to the host[J]. Appl Microbiol Technol. 1992; 37(1): 79-83.
54 Kim S G, Bor Y C, Batt C A. Bacteriophage-resistance in Lactococcus lactis ssp.lactis using antisense ribonucleic acid[J]. J Dairy Sci. 1992; 75(7): 1761-1767.
55 Walker S A, Klaenhammer T R. An explosive antisense RNA strategy for inhibition of a lactococcal bacteriophages]. Appl Enrion Microbiol. 2000; 66(1): 310-319.
56 McGrath S, Fitzgerald G F, van Sinderen D. Improvement and optimization of two engineered phage resistance mechanisms in Lactococcus lactis[J], Appl Environ Microbiol. 2001; 67(2): 608-616.
57 Sturino J M, klaenhammer T R. Expression of antisense RNA against Streptococcus thermophilus bacteriophages[J]. Appl Environ Microbiol. 2002; 68(2): 588-596.
58 Sturino J M, Klaenhammer T R. Antisense RNA targeting primase interferes with bacteriophage replication in Streptococcus thermophilus[J]. Appl Environ Microbiol. 2004; 70(3): 1735-1743.
59 Masse E, Escorcia F E, Gottesman S. Coupled degradation of a small regulatory RNA and its mRNA targets in Escherichia coli[J]. Genes Dev. 2003; 17(19): 2374-2383.
60 Bull J J, Jacobson A, Badgett M R, et al. Viral escape from antisense RNA[J]. Mol Microbiol. 1998; 28(4): 835-846.
61 Hill C, Miller L A, Klaenhammer T R. Cloning, expression, and sequence determination of a bacteriophage fragment encoding bacteriophage resistance in Lactococcus lactis[J]. J Bacteriol. 1990; 172(11): 6419-6426.
62 Sturino J M, Klaenhammer T R. Engineered bacteriophage- defence system in bioprocessing[J]. Nat Rev Microbiol. 2006; 4(1): 395-404.
63 O' Sullivan D J, Hill C, Klaenhammer T R. Effect of increasing the copy number of bacteriophage origins of replication in trans on incoming-phage proliferation[J]. Appl Environ Microbiol. 1993; 59(8): 2449-2456.
64 Foley S, Lucchini S, Zwahlen M C, et al. A short noncoding viral DNA element showing characteristics of a replication origin confers bacteriophage resistance to Streptococcus thermophilus[J]. Virology. 1998; 250(2): 377-387.
65 Djordjevic G M, O'Sullivan D J, Walker S A, et al. A triggered suicide system designed as a defence against bacteriophages [J]. J Bacteriol. 1997; 179(21): 6741-6748.
66 Djordjevic G M, Klaenhammer T R. Bacteriophage-triggered defence systems: phage adaptation and design improvements [J]. App Environ Microbiol. 1997; 63(11): 4370-4376.
67 Moineau S, Walker S A, Holler B J, et al. Expression of a Lactococcus lactis phage resistance mechanism by Streptococcus thermophilus[J] . Appl Environ Microbiol. 1995; 61(7): 2461-2466.
68 Kong J, Josephsen J. The ability of the plasmid-encoded restriction and modification system LlaBIII to protect Lactococcus lactis against bacteriophages [J]. Let Appl Microbiol. 2002; 34(4): 249-253.
69 Herskowitz I. Functional inactivation of genes by dominant negative mutation[J]. Nature. 1987; 329(10): 219-222.
70 Sturino J M, Klaenhammer T R. Bacteriophage defence systems and strategies for lactic acid bacteria. In Advances in Applied Microbiology[M].In: Laskin A I, Bennett J W, Gadd G M (eds.). San Diego: Academic Press, 2005. p. 331-378.
71 Garbutt K C, Kraus J, Geller B L. Bacteriophage resistance in Lactococcus lactis engineered by replacement of a gene for a bacteriophage receptor[J]. J Dairy Sci. 1997; 80(8): 512-1519.
72 Pedersen M B, Jensen P R, Janzen T, et al. Bacteriophage resistance of a thyA mutant of Lactococcus lactis blocked in DNA replication[J]. Appl Environ Microbiol. 2002; 68(6): 3010-3023.
73 Pedersen M B, Koebmann B J, Jensen P R, et al. Increasing acidification of nonreplicating Lactococcus lactis AthyA mutants by incorporating ATPase activity [J]. Appl Environ Microbiol. 2002; 68(6): 5249-5257.
74 Maguin E, Prevost H, Ehrlich S D, et al. Efficient insertional mutagenesis in lactococci and other Gram-positive bacteria[J]. J Bacteriol. 1996; 178(3): 931-935.
75 Lawrence J G, Hendrix R, Casjens S. Where are the pseudogenes in bacterial genomes? [J] Trends Microbiol. 2001; 9(11): 535-540.
76 Briissow H and Hendrix R W. Phage genomics: small is beautiful[J]. Cell. 2002; 108(1): 13-16.
77 Desiere F, Lucchini S, Canchaya C, et al. Comparative genomics of phages and prophages in lactic acid bacteria[J]. Antonie Van Leeuwenhoek. 2002; 82(1-4): 73-91.
78 Bruttin A, Desiere F, Lucchini S, et al. Characterization of the lysogeny DNA module from the temperate Streptococcus thermophilus bacteriophage Sfi21[J]. Virology. 1997; 233(1): 136-148.
79 McGrath S, Fitzgerald G F, van Sinderen D. Identification and characterization of phage-resistance genes in temperate lactococcal bacteriophages [J]. Mol Microbiol. 2002; 43(2): 509-520.
80 Bruttin A, Foley S, Briissow H. DNA-binding activity of the Streptococcus thermophilus phage Sfi21 repressor[J]. Virology. 2002; 303(1): 100-109.
81 O'Sullivan D, Coffey A, Fitzgerald G F, et al. Design of a phage-insensitive lactococcal dairy starter via sequential transfer of naturally occurring conjugative plasmids[J]. Appl Environ Microbiol. 1998; 64(11): 618-4622.
82 Hull R R. Recent developments in the genetics of lactic acid bacteria[J]. CSIRO Food Res Q. 1985; 45: 40-46.
83 Johansen E. Genetic engineering, modification of bacteria. In: Robinson R, Batt C, Patel P (eds). Encyclopedia of Food[M]. London: MicrobiologyAcademic Press, 1999. p.917-912.
2 彭珍荣.微生物资源与氨基酸的生产和应用[J].化学与生物工程.2003;20(6);7-9.
3 袁品坦.再谈噬菌体的污染及其预防[J].发酵科技通讯.1999;28(4);22-27.
4 沈锡辉,刘双江.谷氨酸棒杆菌中芳香化合物降解的β-酮己二酸途径中原儿茶酸分支关键酶的鉴定[J].中国科学(C辑).2004;34(6);547-554.
5 何宁,李寅,陈坚,等.谷氨酸棒杆菌合成新型生物絮凝剂分批发酵过程的溶氧控制模式[J].环境科学学报.2004;24(3);492-497.
6 Salim K,Haedens V,Content J,et al.Heterolgous expression of the Mycobacterium tuberculosis gene encoding antigen 85A in Corynebacterium glutamicum[J].Appl Environ Microbiol.1997;63(11);4392-4400.
7 Puech V,Bayan N,Salim K,et al.Characterization of the in vivo acceptors of the mycolyl residues transferred by the corynebacterial PS1 and the related mycobacterial antigen 85[J].MolMicrobiol.2000;35(5);1026-1041.
8 Sander M E.Bateriophages in industrial fermentations.In;Webster R G.Granoff A(Eds).Encyclopedia of Virology[M].Lodon;Academic Press,1993.p.117-121.
9 袁品坦.谷氨酸菌种选育的进展及其回顾[J].发酵科技通讯.2000;39(1);15-20.
10 杨汝德,张玉榽,陈连就.抗噬菌体突变株U-9的选育[J].发酵科技通讯.1986;(2);49-54.
11 单志萍,吴燕,陆茂林,等.谷氨酸产生菌T6-13抗噬菌体突变株的选育[J].发酵科技通讯.1990;(2);19-23.
12 武标,张千,赫英军,等.抗噬菌体谷氨酸高产菌株选育[J].激光生物学报.2006,15(4);399-412
13 Schafer A,Schwarzer A,Kalinowski J,et al.Cloning and characterization of a DNA region encoding a stress-sensitive restriction system from Corynebacterium glutamicum ATCC 13032 and analysis of its role in intergeneric conjugation with Escherichia coli[J].J Bacteriol. 1994;176(23);7309-7319.
14 Schafer A,Tauch A,Droste N,et al.The Corynebacterium glutamicum cgllM gene encoding a 5-cytosine methyltransferase enzyme confers a specific DNA methylation pattern in an McrBC-deficient Escherichia coli strain[J].Gene.1997;203(2);95-101.
15 陆军,唐炯,张文波,等.棒状杆菌表达载体pJL23的构建[J].复旦学报(自然科学版).2000;39(3);292-296.
16 Sambrook J,Rusell D W.Molecular cloning;A laboratory Manual,3rd Ed[M].In;Cold Spring Harbor.New York;Cold Spring Harbor Laboratory Press,2001.
17 余茂效,司穉东.噬菌体实验技术[M].北京;科学出版社,1991.p.11-12.
18 Kong J,Josephsen J.The ability of the plasmid-encoded restriction and modification system LlaBⅢ to protect Lactococcus lactis against bacteriophages[J].Lett Appl Microbiol.2002;34(4);249-253.
19 Kobayashi I.Behavior of restriction-modification systems as selfish mobile elements and their impact on genome evolution[J].Nucleic Acids Research.2001;29(18);3742-3756.
20 Roberts R J.Restriction and modification enzymes and their recognition sequences[J].Gene.1978;4;183-193.
21 Roberts R J,Vincze T,Posfal J,et al.REBASE - restriction enzymes and DNA methyltransferases[J].Nucleic Acids Research.2005;33(Database Issue);230-232.
22 Pingoud A,Fuxreiter M,Pingoud V,et al.Type II restriction endonucleases;structure and mechanism[J].Cell Mol Life Sci.2005;62(6);685-707.
23 Roberts R J,Belfort M,Bestor T,et al.A nomenclature for restriction enzymes,DNA methyltransferases,homing endonucleases and their genes[J].Nucleic Acid Res.2003;31(7);805-1812.
24 Lin L F,Posfai J,Robert R J,et al.Comparative genomics of therestriction -modification systems in Helicobacterpylori[J].Proc Natl Acad Sci USA.2001;98(5);2740-2745.
25 Izsvak Z,Jobbagy Z,Takacs I,et al.Cloning and characterization of the gene of the ceqI restriction-modification system[J].J Biochem Cell Biol.1997;29(6);895-900.
26 Mann M B,Rao R N,Smith H O.Cloning of restriction and modification genes in E.coli;the Hba II system from Haemophilus haemolyticus[J]. Gene. 1978; 3(2): 97-112.
27 Xu S Y, Xiao J P, Ettwiller L, et al. Cloning and expression of the ApaLI, NspI, NspHI, SacI, ScaI, and SapI restriction-modification systems in Escherichia coli[J]. Mol Gen Genet. 1998; 260(2-3): 226-231.
28 Meselson M, Yuan R. DNA restriction enzyme from E. coli[J]. Nature. 1968; 3(23): 1110 -1114.
29 Zhu Z Y, Robinson D, Benne J, et al. Method for cloning and expression of Tth111 II restriction endonuclease-methylase in E. coli[P]. USA, Invent. Patent, No. 6919194. 2004.
30 Howard K A, Card C, Benner J S, et al. Cloning the Ddel restriction-modification system using a two-step method[J]. Nucleic Aci Res. 1986; 14(20): 7939-7951.
31 Brooks J E, Benner J S, Silber K R, et al. Cloning and characterization of the BamHI restriction modification system[J]. Gene. 1988; 74(1): 13.
32 Zhu Z Y, Xu S Y. Method for cloning and expression of BsaI restriction endonuclease and BsaI methylase in E. coli[?]. USA, Invent. Patent, No.6723546. 2004.
33 Xu S Y, Maunus R, Stropnicky K. Method for cloning and expression of MspAll restriction endonuclease and MspAll methylase in E.coli[P]. USA, Invent. Patent, No.6673588. 2004.
34 Elisabeth A, Raleigh, Wilson G. Escherichia coli K-12 Restricts DNA Containing 5-methylcytosine[J]. PNAS. 1986; 83(23): 9070-9074.
35 Heitman J, Model P. Site-specific methylases induce the SOS DNA repair response in Escherichia coli[i]. J Bacteriol. 1987; 69(7): 3243-3250.
36 Raleigh E A. Organization and function of the mcrBC genes of Escherichia coli K-12 [J]. Mol Microbiol. 1992; 6(9): 1079-1086.
37 Tauch A, Homann I, Mormann S, et al. Strategy to sequence the genome of Corynebacterium glutamicum ATCC 13032: use of a cosmid and a bacterial artificial chromosome library[J]. J Biotechnol. 2002; 95(1): 25-38.
38 Nakayama Y, Kobayashi I. Restriction-modification gene complexes as selfish gene entities: Roles of a regulatory system in their establishment, maintenance, and apoptotic mutual exclusion[J]. Proc Nat Acad Sci USA. 1998; 95(11): 6442-6447.
39 Kobayashi I.DNA modification and restriction;Selfish behavior of an epigenetic system.In;Russo V,Martienssen R,Riggs A(eds.).Epigenetic mechanisms of gene regulation[M].New York;Cold Spring Harbor Laboratory Press,1996.p.155-172.
40 Knowle D,Lintner R E,Touma Y M,et al.Nature of the Promoter Activated by C.Pvu II,an Unusual Regulatory Protein Conserved among Restriction-Modification Systems[J].J Bacteriol.2005;187(2);488-497.
41 Kobayashi I.Restriction-modification systems as minimal forms of life.In;Pingoud A.(ed.),Restriction endonucleases[M].Berlin,Germany;Springer-Verlag,2004.p;19-62.
42 Murray N E.Immigration control of DNA in bacteria;Self versus non-self[J].Microbiology.2002;148(1);3-20.
43 McGeehan J E,Papapanagiotou I,Streeter S D,et al.Cooperative binding of the C.AhdI controller protein to the C/R promoter and its role in endonuclease gene expression[J].Mol Biol.2006;358(1);523-531.
44 王家驯,朱素娟,戈宝榛,等.谷氨酸生产菌株T6-13噬菌体的分离及其血清型分布[J].工业微生物.1990;20(4);6-9.
45 袁品坦.谷氨酸发酵中噬菌体污染的防治[J].发酵科技通讯.1992;2(1);46-52.
46 邱炜炜,林有波,谢天阳.预防噬菌体污染的有效方法[J].发酵科技通讯.2000;29(1);38-39.
47 Coffey A,Ross R P.Bacteriophage-resistance systems in dairy starter strains;molecular analysis to application[J].Antonie van Leeuwenhoek.2002;82(1-4);303-321.
48 Forde A,Fitzgerald G F.Bacteriophage defense systems in lactic acid bacteria[J].Antonie van Leeuwenhoek.1999;76(1-4);89-113.
49 Lucchini S,Sidoti J,Brussow H.Broad-range bacteriophage resistance in Streptococcus thermophilus by insertional mutagenesis[J].Virology.2000;275(2);267-272.
50 余秉琦,沈微,诸葛健.适用于异源DNA高效整合转化的谷氨酸棒杆菌电转化法[J].中国生物工程杂志.2005;25(2);78-81.
51 Klaenhammer T R.Genetic characterization of multiple mechanisms of phage defense from a prototype phage-insensitive strain Lactococeus laetis ME2[J].J Dairy Sci.1989;72; 3429-3443.
52 Klaenhammer T R,Romero D,Sing W,et al.Molecular analysis of pTR2030 gene systems that confer phage resistance to lactococci.In;Dunny G,Cleary P,McKay L(eds.).Genetics and Molecular Biology of Streptococci,Lactococci,and Enterococci[M].Washington,DC;American Society for Microbiology Press,1991.p.124-130.
53 Duckworth D H,Glenn J,McCorquodale D J.Inhibition of bacteriophage replication by extra-chromosomal elements[J].Microbiol Rev.1981;45(1);52-71.
54 McGrath S,Seegers J F M L,Fitzgerald G F,et al.Molecular Characterization of a Phage-Encoded Resistance System in Lactococcus lactis[J].Appl Environ Microbiol.1999;65(5);1891-1899.
55 Sturino J M,Klaenhammer T R.Engineeried Bacteriophage- defence systems in bioprocessing[J].Microbiology.2006;4(10);395-404.
56 Moineau S,Emond E,Walker S A,et al.DNA encoding phage resistance protein[P].USA,Invent.Patent,No.5994118.1999.
57 Mollet B,Pridmore D,Zwahlen M C.Phage-resistant streptococcus[P].USA,Invent.Patent,No.5766904.1998.
58 Moineau S,Walker S A,Vedamuthu E R,et al.Enzyme for phage resistance[P].USA,Invent.Patent,No.5972673.1999.
59 韦平和,吴梧桐.色氨酸生物工程研究进展[J].药物生物技术.1998;5(3);180-185.
60 Cases I,Lorenzo V D.Genetically modified organisms for the environment;Stories of success and failure and what we have learned from them[J].Int Microbiol.2005;8(3);213-222.
61 喻国策,焦瑞身,王骥程等.大肠杆菌HBl01(pBR322)高密度培养过程质粒的稳定性[J].过程工程学报.2001;1(2);185-189.
62 Friehs K.Plasmid copy number ahd plasmid stability[J].Adv Biochem Eng Biotechnol.2004;86(10);47-82.
63 Friehs K,Reardon K F.Parameters influencing the productivity of recombinant E.coli cultivations[J].Adv Biochem Eng Biotechnol.1993;48(10);53-77.
64 Gerdes K, Jacobsen J S, Franch T. Plasmid stabilization by post -segregational killing[J]. Genet Eng. 1997; 19(1): 49-61.
65 Kobayashi I. Genetic addiction: a principle in symbiosis of genes in a genome, In Funnel B E, Phillips G J (eds.). Plasmid biology[M]. Washington, D.C: ASM Press, 2004. p. 105-144.
66 Koyama A H, Wada C, Nagata T, et al. Indirect selection for plasmid mutants: Isolation of ColVBtrp mutants defective in self-maintenance in Escherichia coli[J]. J Bacteriol. 1975; 122(1): 73-79.
67 Gerdes K. Toxin-antitoxin modules may regulate synthesis of macromolecules during nutritional stress[J]. J Bacteriol. 2000; 182(3): 561-572.
68 Gerdes K, Gultyaev A P, Franch T, et al. Antisense RNA-regulated programmed cell death[J]. Annu Rev Genet. 1997; 31(10): 1-31.
69 Zielenkiewicz U, Ceglowski P. Mechanisms of plasmid stable maintenance with special focuson plasmid addiction system[J]. Acta Biochimica Polonica. 2001; 48(4): 1003-1023.
70 Naito T, Kusano K, Kobayashi I. Selfish behavior of restriction-modification systems [J]. Science. 1995; 267(5199): 897-899.
71 Kulakauskas S, Lubys A, Ehrlich S D. DNA restriction- modification systems mediate plasmid maintenance[J]. J Bacteriol. 1995; 177(12): 3451-3454.
72 Kusano K, Naito T, Handa N, et al. Restriction-modification systems as genomic parasites in competition for specific sequences[J]. Proc Natl Acad Sci USA. 1995; 92(24): 11095-11099.
73 Handa N, Kobayashi I. Post-segregational killing by restriction modification gene complexes: observations of individual cell deaths[J]. Biochimie. 1999; 81(8-9): 931-938.
74 Handa N, Ichige A, Kusano K, et al. Cellular responses to postsegregational killing by restriction-modification genes[J]. J Bacteriol. 2000; 182(8): 2218-2229.
75 Chinen A, Naito Y, Handa N, et al. Evolution of sequence recognition by restriction-modification enzymes: selective pressure for specificity decrease[J]. Mol Biol Evol.2000; 17(11): 1610-1619.
76 Takahashi N, Naito Y, Handa N, et al. A DNA methyltransferase can protect the genome from postdisturbance attack by a restriction-modification gene complex[J]. J Bacteriol. 2002; 184(22);6100-6108.
77 Patnaik P R.An evaluation of models for the effect of plasmid copy number on bacterial growth rate[J].Biotechnol Lett.2000;22(21);1719-1725.
78 天津轻工业学院,大连轻工业学院,无锡轻工大学,等.工业发酵分析[M].北京;中国轻工业出版社,2004.p.99-108.
79 葛保胜,任育红,唐志红,等.表达重组别藻蓝蛋白质粒在工程菌株中的遗传稳定性研究[J].微生物学通报.2005;32(4);37-41.
80 沈萍,范秀容,李广武.微生物学实验(第三版)[M].北京;高等教育出版社,1999.D.141-143.
81 Ricci J C D,Hemandez M E.Plasmid effects on Escherichia coli metabolism[J].Crit Rev Biotechnol.2000;20(2);79-108.
82 Lee K,Moon S H.Growth kinetics of Lactococcus lactis ssp.diacetylactis harboring different plasmid content[J].Curr Microbiol.2003;47(1);17-21.
83 崔卫国,聂风强.提高谷氨酸发酵产酸水平的研究[J].发酵科技通讯.2001;30(2);1-2.
84 Casadesus J,Low D.Epigenetic gene regulation in the bacterial world[J].Microbiol Mol Biol Rev.2006;70(3);830-856.
1 Twort F.An investigation on the nature of ultramicroscopic viruses[J].Lancet.1915;2;1241-1243.
2 D'Herelle F.Sur un microbe invisible antagoniste des bacilles dysenteriques[J].Comp Rend Acad Sci.1917;165;373-375.
3 Maniloff J,Cadden S P,Putzrath R M.Maturation of an enveloped budding phage;Mycoplasmavirus L2[J].Prog Clin Biol Res.1981;64;503-513.
4 Sable S,Lortal S.The lysins of bacteriophages infecting lactic acid bacteria[J].Appl Microbiol Biotechnol.1995;43(11);1-6.
5 Wang I N,Smith D L,Young R.Holins;The protein clocks of bacteriophage infections[J].Annu Rev Microbiol.2000;54(1);799-825.
6 Madera C,Monjardin C,Suarez J E.Milk contamination and resistance to processing conditions determine the fate of Lactococcus lactis bacteriophages in dairies[J].Appl Environ Microbiol.2004;70(12);7365-7371.
7 袁品垣.再谈噬菌体的污染及其预防[J].发酵科技通讯.1999;28(4);22-27.
8 修文琼,列书锋,何爱华,等.福建各地抗生素厂生产菌株污染噬菌体的电镜监测[J].海峡预防医学杂志.2000;6(6);41-42.
9 李英朝,李艳,贾宁,等.维生素B12生产中噬菌体污染的检查与预防[J].河北工业科技.2000;17(4);42-48.
10 赵峰梅,孙文敬,米丽娟,等.噬菌体污染对荧光假单胞菌K1005 2-酮基-D-葡萄糖酸发酵的影响[J].食品科学.2002;23(6);72-74.
11 Huggins A R,Sandine W E.Selection and charaterization of phage insensitive Lactic streptococci[J].J Dairy Sci.1979;62;70-71.
12 Klaenhammer T R.Interaction of bacteriophage with Lactic streptococci[J].Adv Appl Microbiol.1984;30(1);1-29.
13 Sandine W E.Use of bacteriophage-resistant mutants of lactococcal starters in cheese-making[J]. Neth Milk Dairy J. 1989; 43:211 -219.
14 Bester B H, Lombard S H. Protection of starter cultures against bacteriophages by propagation in a phage-resistant medium[J]. South African J Dairy Technol. 1975; 7: 235-450.
15 Gulstrom T J, Pearce L E, Sandine W E, et al. Evaluation of commercial phage inhibitory media[J]. J Dairy Sci. 1979; 62: 208-221.
16 Daly C. The use of mesophilic cultures in the dairy industry[J]. Antonie Van Leeuwenhoek. 1983; 49(3): 297-312.
17 Lowrie R J, Pearce L E. The plating efficiency of bacteriophages of Lactic streptococci[J]. N Z J Dairy Sci Technol. 1971; 6: 166-171.
18 Lubbers M W, Waterfield N R, Beresford T P, et al. Sequencing and analysis of the prolate-headed lactococcal bacteriophage c2 genome and identification of the structural genes[J]. Appl Environ Microbiol. 1995; 61(12): 4348-4356.
19 Coffey A, Ross R P, Bacteriophage-resistance systems in dairy starter strains: molecular analysis to application[J]. Antonie Van Leeuwenhoek. 2002; 82(1-4): 303-321.
20 Forde A, Fitzgerald G F. Bacteriophage defense systems in lactic acid bacteria[J]. Antonie Van Leeuwenhoek. 1999; 76(1-4): 89-113.
21 Lucchini S, Sidoti J, Bru ssow H. Broad-range bacteriophage resistance in Streptococcus thermophilus by insertional mutagenesis[J]. Virology. 2000; 275(2): 267-272.
22 Budde-Niekiel A, Teuber M. Electron microscopy of the adsorption of bacteriophages to lactic acid streptococci[J]. Milchwissenschaft. 1987; 42: 551-553.
23 Quiberoni A, Stiefel L I, Reinheimer J A . Characterization of phage receptors in Streptococcus thermophilus using purified cell walls obtained by a simple protocol[J]. J Appl Microbiol. 2000; 89(6): 1059-1065.
24 Klaenhammer T R, Fitzgerald G F. Bacteriophage and bacteriophage resistance. In : Gasson M J, de Vos W M (eds.). Genetics and Biotechnology of Lactic Acid Bacteria [M]. London: Chapman and Hall, 1994. p. 106-168.
25 Broadbent J R, McMahon D J, Welker D L, et al. Biochemistry, genetics, and applications of exopolysaccharide production in Streptococcus thermophilus: A review[J]. J Dairy Sci. 2003; 86(2): 407-423.
26 Klaenhammer T R. Genetic characterization of multiple mechanisms of phage defense from a prototype phage-insensitive strain Lactococcus lactis ME2[J]. J Dairy Sci. 1989; 72: 3429-3443.
27 Klaenhammer T R, Romero D, Sing W, et al. Molecular analysis of pTR2030 gene systems that confer phage resistance to lactococci. In: Dunny G, Cleary P, and McKay L(eds.). Genetics and Molecular Biology of Streptococci, Lactococci, and Enterococci[M]. Washington, DC : American Society for Microbiology Press, 1991. p. 124-130.
28 Roberts R J, Belfort M, Bestor T, et al. A nomenclature for restriction enzymes, DNA methyltransferases, homing endonucleases and their genes[J]. Nucleic Acids Res. 2003; 31(7): 1805-1812.
29 Moineau S, Pandian S, Klaenhammer T R. Restriction/ modification systems and restriction endonucleases are more effective on lactococcal bacteriophages that have emerged recently in the dairy industry[J]. Appl Environ Microbiol. 1993; 59(1):197-202.
30 Powell I A, Davidson B E. Resistance to in vitro restriction of DNA from Lactic streptococcal bacteriophage c6A[J]. Appl Environ Microbiol. 1986; 51:1358-1360.
31 Wilson G G, Murray N E. Restriction and modification systems[J]. Annu Rev Genet. 1991; 25(10): 585-627.
32 Bickle T A, Kruger D H. Biology of DNA restriction[J]. Microbiol Rev. 1993; 57(2): 434-450.
33 Hill C, Miller L A, Klaenhammer T R. In vivo genetic exchange of a functional domain from a type IIA methylase between lactococcal plasmid pTR2030 and a virulent bacteriophage[J]. J Bacteriol. 1991; 173(14): 4363-4370.
34 Klaenhammer T R, Sanozky R. Conjugal transfer from Streptococcus lactis ME2 of plasmids encoding phage resistance, nisin resistance and lactosefermenting ability: Evidence for a high-frequency conjugative plasmid responsible for abortive infection of virulent bacteriophage[J]. J Gen Microbiol. 1985; 131(2): 1531-1541.
35 Sing W D, Klaenhammer T R. A strategy for rotation of different bacteriophage defenses in a lactococcal single-strain starter culture system[J]. Appl Environ Microbiol. 1993; 59(2): 365-372.
36 Durmaz E, Klaenhammer T R. A starter culture rotation strategy incorporating paired restriction/modification and abortive infection bacteriphage defenses in a single Lactococcus lactis strain[J]. Appl Environ Microbiol. 1995; 61(4): 1266-1273.
37 Burrus V, Bontemps C, Decaris B, et al. Characterization of a novel type II restriction-modification system, Sth368I, encoded by the integrative element ICEStl of Streptococcus thermophilus CNRZ368[J]. Appl Environ Microbiol. 2001; 67(4): 1522-1528.
38 Poch M T, Somkuti G A , Solaiman D K Y. Sthl32I, a novel class-IIS restriction endonuclease of Streptococcus thermophilus ST132[J]. Gene. 1997; 195(2): 201-206.
39 Duckworth D H, Glenn J, McCorquodale D J. Inhibition of bacteriophage replication by extra-chromosomal elements[J]. Microbiol Rev. 1981; 45: 52-71.
40 Allison G E , Klaenhammer T R. Phage resistance mechanisms in lactic acid bacteria[J]. Int Dairy J. 1998; 8(3): 207-226.
41 Casey J, Daly C, Fitzerald G F. Controlled integration into the Lactococcus chromosome of the pCI829-encoded abortive infection gene from Lactococcus lactis subsp.lactis UC811[J]. Appl Environ Microbiol. 1992; 58(10): 3283-3291.
42 Dinsmore P K, Klaenhammer T R. Phenotypic consequences of altering the copy number of abiA, a gene responsible for aborting bacteriophage infections in Lactococcus lactis[J]. Appl Environ Microbiol. 1994; 60(4): 1129-1136.
43 Garvey P, van Sinderen D, Twomey D P, et al. Molecular genetics of bacteriophage and natural phage defense systems in the genus Lactococcus[J]. Int Dairy J. 1995; 5(1): 905-947.
44 Sanders M E, Klaenhammer T R. Characterization of phage-sensitive mutants from a phage-insensitive strain of Streptococcus lactis: evidence for a plasmid determinant that prevents phage adsorption[J]. Appl Environ Microbiol. 1983; 46: 1125-1133.
45 Chopin A, Chopin M C, Moillo-Batt A, et al. Two plasmid- determined restriction and modification systems in Streptococcus lactis[J] . Plasmid. 1984; 11: 260-263.
46 Froseth B R, Harlander S K and McKay L L. Plasmid-mediated reduced phage sensitivity in Streptococcus lactis KR5[J]. J Dairy Sci. 1988; 71: 275-284.
47 Durmaz E, Higgins D L, Klaenhammer T R. Molecular characterization of a second abortive phage resistance gene present in Lactococcus lactis subsp.lactis ME2[J]. J Bacteriol. 1992; 174(22): 7463-7469.
48 Higgins D L, Sanozky-Dawes R B, Klaenhammer T R. Restriction and modification activities from Streptococcus lactis ME2 are encoded by a self-transmissible plasmid, pTN20, that forms cointegrates during mobilization of lactose-fermenting-ability[J]. J Bacteriol. 1988; 170(8): 3435-3442.
49 Hill C, Massey I J, Klaenhammer T R. Rapid method to characterize lactococcal bacteriophage genomes[J]. Appl Environ Microbiol. 1991; 57(1): 283-288.
50 Coleman J, Hirashima A, Inokuchi Y, et al. A novel immune system against bacteriophage infection using complementary RNA(micRNA) [J]. Nature. 1985; 315(6020): 601-603.
51 Kim S G, Batt C A. Antisense mRNA-mediated bacteriophage-resistance in Lactococcus lactis ssp.lactis[J]. Appl Environ Microbiol. 1991; 57(4): 1109-1113.
52 Chung D K, Kim J H, Batt C A. Cloning and nucleotide sequence of the major capsid protein from Lactococcus lactis ssp.cremoris bacteiophage F4-1[J]. Gene. 1991; 101(1): 121-125.
53 Chung D K, Chung S K, Batt C A. Antisense RNA directed against the major capsid protein from Lactococcus lactis ssp.cremoris bacteriophage F4-1 confers partial resistance to the host[J]. Appl Microbiol Technol. 1992; 37(1): 79-83.
54 Kim S G, Bor Y C, Batt C A. Bacteriophage-resistance in Lactococcus lactis ssp.lactis using antisense ribonucleic acid[J]. J Dairy Sci. 1992; 75(7): 1761-1767.
55 Walker S A, Klaenhammer T R. An explosive antisense RNA strategy for inhibition of a lactococcal bacteriophages]. Appl Enrion Microbiol. 2000; 66(1): 310-319.
56 McGrath S, Fitzgerald G F, van Sinderen D. Improvement and optimization of two engineered phage resistance mechanisms in Lactococcus lactis[J], Appl Environ Microbiol. 2001; 67(2): 608-616.
57 Sturino J M, klaenhammer T R. Expression of antisense RNA against Streptococcus thermophilus bacteriophages[J]. Appl Environ Microbiol. 2002; 68(2): 588-596.
58 Sturino J M, Klaenhammer T R. Antisense RNA targeting primase interferes with bacteriophage replication in Streptococcus thermophilus[J]. Appl Environ Microbiol. 2004; 70(3): 1735-1743.
59 Masse E, Escorcia F E, Gottesman S. Coupled degradation of a small regulatory RNA and its mRNA targets in Escherichia coli[J]. Genes Dev. 2003; 17(19): 2374-2383.
60 Bull J J, Jacobson A, Badgett M R, et al. Viral escape from antisense RNA[J]. Mol Microbiol. 1998; 28(4): 835-846.
61 Hill C, Miller L A, Klaenhammer T R. Cloning, expression, and sequence determination of a bacteriophage fragment encoding bacteriophage resistance in Lactococcus lactis[J]. J Bacteriol. 1990; 172(11): 6419-6426.
62 Sturino J M, Klaenhammer T R. Engineered bacteriophage- defence system in bioprocessing[J]. Nat Rev Microbiol. 2006; 4(1): 395-404.
63 O' Sullivan D J, Hill C, Klaenhammer T R. Effect of increasing the copy number of bacteriophage origins of replication in trans on incoming-phage proliferation[J]. Appl Environ Microbiol. 1993; 59(8): 2449-2456.
64 Foley S, Lucchini S, Zwahlen M C, et al. A short noncoding viral DNA element showing characteristics of a replication origin confers bacteriophage resistance to Streptococcus thermophilus[J]. Virology. 1998; 250(2): 377-387.
65 Djordjevic G M, O'Sullivan D J, Walker S A, et al. A triggered suicide system designed as a defence against bacteriophages [J]. J Bacteriol. 1997; 179(21): 6741-6748.
66 Djordjevic G M, Klaenhammer T R. Bacteriophage-triggered defence systems: phage adaptation and design improvements [J]. App Environ Microbiol. 1997; 63(11): 4370-4376.
67 Moineau S, Walker S A, Holler B J, et al. Expression of a Lactococcus lactis phage resistance mechanism by Streptococcus thermophilus[J] . Appl Environ Microbiol. 1995; 61(7): 2461-2466.
68 Kong J, Josephsen J. The ability of the plasmid-encoded restriction and modification system LlaBIII to protect Lactococcus lactis against bacteriophages [J]. Let Appl Microbiol. 2002; 34(4): 249-253.
69 Herskowitz I. Functional inactivation of genes by dominant negative mutation[J]. Nature. 1987; 329(10): 219-222.
70 Sturino J M, Klaenhammer T R. Bacteriophage defence systems and strategies for lactic acid bacteria. In Advances in Applied Microbiology[M].In: Laskin A I, Bennett J W, Gadd G M (eds.). San Diego: Academic Press, 2005. p. 331-378.
71 Garbutt K C, Kraus J, Geller B L. Bacteriophage resistance in Lactococcus lactis engineered by replacement of a gene for a bacteriophage receptor[J]. J Dairy Sci. 1997; 80(8): 512-1519.
72 Pedersen M B, Jensen P R, Janzen T, et al. Bacteriophage resistance of a thyA mutant of Lactococcus lactis blocked in DNA replication[J]. Appl Environ Microbiol. 2002; 68(6): 3010-3023.
73 Pedersen M B, Koebmann B J, Jensen P R, et al. Increasing acidification of nonreplicating Lactococcus lactis AthyA mutants by incorporating ATPase activity [J]. Appl Environ Microbiol. 2002; 68(6): 5249-5257.
74 Maguin E, Prevost H, Ehrlich S D, et al. Efficient insertional mutagenesis in lactococci and other Gram-positive bacteria[J]. J Bacteriol. 1996; 178(3): 931-935.
75 Lawrence J G, Hendrix R, Casjens S. Where are the pseudogenes in bacterial genomes? [J] Trends Microbiol. 2001; 9(11): 535-540.
76 Briissow H and Hendrix R W. Phage genomics: small is beautiful[J]. Cell. 2002; 108(1): 13-16.
77 Desiere F, Lucchini S, Canchaya C, et al. Comparative genomics of phages and prophages in lactic acid bacteria[J]. Antonie Van Leeuwenhoek. 2002; 82(1-4): 73-91.
78 Bruttin A, Desiere F, Lucchini S, et al. Characterization of the lysogeny DNA module from the temperate Streptococcus thermophilus bacteriophage Sfi21[J]. Virology. 1997; 233(1): 136-148.
79 McGrath S, Fitzgerald G F, van Sinderen D. Identification and characterization of phage-resistance genes in temperate lactococcal bacteriophages [J]. Mol Microbiol. 2002; 43(2): 509-520.
80 Bruttin A, Foley S, Briissow H. DNA-binding activity of the Streptococcus thermophilus phage Sfi21 repressor[J]. Virology. 2002; 303(1): 100-109.
81 O'Sullivan D, Coffey A, Fitzgerald G F, et al. Design of a phage-insensitive lactococcal dairy starter via sequential transfer of naturally occurring conjugative plasmids[J]. Appl Environ Microbiol. 1998; 64(11): 618-4622.
82 Hull R R. Recent developments in the genetics of lactic acid bacteria[J]. CSIRO Food Res Q. 1985; 45: 40-46.
83 Johansen E. Genetic engineering, modification of bacteria. In: Robinson R, Batt C, Patel P (eds). Encyclopedia of Food[M]. London: MicrobiologyAcademic Press, 1999. p.917-912.