CN107033246A - 一种能从菌体外裂解大肠杆菌的融合裂解酶 - Google Patents

一种能从菌体外裂解大肠杆菌的融合裂解酶 Download PDF

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CN107033246A
CN107033246A CN201611202035.9A CN201611202035A CN107033246A CN 107033246 A CN107033246 A CN 107033246A CN 201611202035 A CN201611202035 A CN 201611202035A CN 107033246 A CN107033246 A CN 107033246A
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雷连成
闫广谋
王爽
吕蒙
朱日宁
马强
顾敬敏
孙长江
冯新
韩文瑜
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Abstract

本发明公开了一种能从菌外杀灭大肠杆菌的融合裂解酶，同时还提供了其构建方法，利用生物技术把大肠杆菌素部分转运区域与一种噬菌体裂解酶融合在一起，即将Colicin A的结合区域、识别区（BR）与裂解酶融合在一起，构建成一种从菌体外直接杀灭大肠杆菌的融合裂解酶，融合蛋白表现出了杀菌作用，能从菌外裂解大肠杆菌，解决了当前噬菌体裂解酶不能从体外裂解大肠杆菌的难题。

Description

一种能从菌体外裂解大肠杆菌的融合裂解酶
技术领域
本发明公开了一种能从菌外杀灭大肠杆菌的融合裂解酶，同时还提供了其构建方法，克服了噬菌体裂解酶不能从菌外杀灭大肠杆菌的缺陷，本发明属于生物制药领域。
背景技术
大肠杆菌是引发人和动物消化道疾病主要病原之一。由于抗生素的大量、广泛的不规范应用，致使大量致病性大肠杆菌产生了多重的耐药性。“超级大肠杆菌”在牧场与自然界已经广泛存在。致病性大肠杆菌的耐药性严重危害着食品安全与公共卫生安全。
噬菌体及其裂解酶制剂，被认为是解决细菌多重耐药性的有效制剂。现在已经有多种噬菌体裂解酶制剂应用于实践，并且有较好的治疗效果。噬菌体裂解酶主要作用细胞壁上肽聚糖而裂解细菌。革兰氏阳性菌的肽聚糖暴露在细胞壁外，因此这些制剂一般应用于革兰氏阳性菌引发的疾病的治疗，比如金黄葡萄球菌病，链球菌病等。大肠杆菌细胞壁的最外层是外膜蛋白，大肠杆菌的外膜蛋白形成的桶状通道，仅允许小分子物质通过，进行细菌的物质代谢交换。大肠杆菌的肽聚糖位于细胞壁里层的周质空间。由于裂解酶是大分子物质，无法从菌外通过外膜蛋白的屏障，进入周质空间，与肽聚糖发生作用，而裂解细胞，因而还没有裂解酶制剂应用于大肠杆菌病的治疗。经检索未见噬菌体裂解制剂应用与革兰氏阴性菌，包括大肠杆菌的文献报道。
发明内容
本发明的公开一种能从体外裂解大肠杆菌的融合裂解酶，把Colicin A的结合区域、识别区（BR）与裂解酶融合在一起，融合蛋白表现出了杀菌作用，能从菌外裂解大肠杆菌，解决了当前噬菌体裂解酶不能从体外裂解大肠杆菌的难题。
本发明还提供了上述融合裂解酶的构建方法。
本发明一种从菌体外直接杀灭大肠杆菌的融合裂解酶（简称：Colicin-lysis），其特征在于：
是由大肠杆菌素的转运片段与噬菌体裂解酶在基因水平融合后表达的重组蛋白：所述的大肠杆菌素的转运片段氨基酸序列如SEQ NO.1 所示，噬菌体裂解酶氨基酸序列为SEQNO.2 序列所示，融合裂解酶氨基酸序列为SEQ NO.3所示。
本发明所述的一种从菌体外直接杀灭大肠杆菌的融合裂解酶构建方法，包括以下步骤：
1）用PCR的方法克隆出把大肠杆菌素的转运片段(SEQ NO.1)的基因，连载的T-载体上，构建成重组质粒pUC-colicin；
2）用PCR的方法克隆出把噬菌体裂解酶的基因(SEQ NO.2) 的基因，连载的pUC-colicin，的大肠杆菌素的转运片段的下游，构建成重组质粒pUC-lysis
3）用内切酶把融合的大肠杆菌素的转运片段与噬菌体裂解酶（SEQ NO.3）的基因切下，并回收。把回收产物连接到原核表达载体pET-28上，构建成重组原核表达载体pET-lysis
4）把pET-lysis转化到大肠杆菌中，IPTG诱导表达融合裂解酶，并纯化。
本发明积极效果在于：
利用生物技术把大肠杆菌素部分转运区域与一种噬菌体裂解酶融合在一起，即将Colicin A的结合区域、识别区（BR）与裂解酶融合在一起，构建成一种从菌体外直接杀灭大肠杆菌的融合裂解酶，融合蛋白表现出了杀菌作用，能从菌外裂解大肠杆菌，解决了当前噬菌体裂解酶不能从体外裂解大肠杆菌的难题。
附图说明
图1为本发明pH值Colicin-lysis杀菌效果影响测定；当pH值等于5的时候，Colicin-lysis杀菌效果为最佳，能把1×105cfu大肠杆菌，杀灭到仅剩余900左右；
图2为本发明对Colicin-lysis杀菌效果影响测定；在16~8ug范围内，理解效果基本稳定，而后随着剂量的减少，裂解细菌的能力而减弱，当剂量2ug时，基本没有杀菌效果；
图3为Colicin-lysis与细菌的作用时间对裂解细菌的影响当作用15分钟是，裂解效果逐渐趋于平稳；
图4为本发明融合裂解酶电泳图。
实施方式
下列实施例旨在进一步举例说明，而不是限制本发明。本领域技术人员可以理解到，在不背离本发明的精神和原则的前提下，对本发明的任何平行改变和改动都将落入本发明的待批权利要求范围内。
实施例1
一、融合裂解酶的构建及纯化
用PCR的方法克隆出把大肠杆菌素的转运片段(SEQ NO.1)的基因，连载的T-载体上，构建成重组质粒pUC-colicin,用PCR的方法克隆出把噬菌体裂解酶的基因(SEQ NO.2) 的基因，连载的pUC-colicin，的大肠杆菌素的转运片段的下游，构建成重组质粒pUC-lysis。用内切酶把融合的大肠杆菌素的转运片段与噬菌体裂解酶（SEQ NO.3）的基因切下，并回收。把回收产物连接到原核表达载体pET-28a上，构建成重组原核表达载体pET-lysis。把pET-lysis转化到BL21(DE3) condon Plus RIPL中。细菌在37℃生长到对数生长期（OD=0.45），加入IPTG诱导后，含有Colicin-lysis基因载体的细菌培养物，在加入IPTG2个小时之后，会在某个时间突然变清；为了收集大量的Colicin-lysis，控制条件，让Colicin-lysis均已包涵体表达；而后分别收集包涵体、复性。通过Ni2+柱（HisTrap FF，GB）亲和层析纯化。融合裂解酶的电泳图件图4。
二、Colicin-lysis体外杀菌性能的测定
实验表明，环境中的pH值Colicin-lysis杀菌效果影响特别大（图1）；37℃条件下，100ug 的Colicin-lysis在 pH=3、浓度为0.02mM的HCl-Tris的缓冲液里，与大肠杆菌作用15分钟，杀菌效果极低，缓冲液里仍能保留大量的细菌。当pH=5时，它的杀菌效果极佳，在相同的条件下，能把1×105cfu个细菌的杀灭到仅有900cfu左右；在pH=5~8之间，随着pH值的升高，杀菌能力，也随着下降；
Colicin-lysis与抗生素不一样，很难测定它的MIC值，因为Colicin-lysis杀菌受环境影响很大。每一个pH值，它的裂解细菌的能力也不相同，我们测定当pH=5时，Colicin-lysis的剂量为3.6ug仍然能有部分杀菌效果，再小于这个剂量，很难观察到它有杀菌效果（图2）；
细菌的作用时间也影响着它的杀菌效果。取剂量100ug，在pH=5的条件下，它的杀菌性能，随时的延长而增强，当作用时间为15min时，达到平衡，时间在延长，也不能增加杀菌效果（图3）。
<110> 吉林大学
<120> 一种能从菌体外裂解大肠杆菌的融合裂解酶
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Claims (2)

1.一种从菌体外直接杀灭大肠杆菌的融合裂解酶，简称：Colicin-lysis；其特征在于：
是由大肠杆菌素的转运片段与噬菌体裂解酶在基因水平融合后表达的融合裂解酶：所述的大肠杆菌素的转运片段氨基酸序列如SEQ NO.1 所示，噬菌体裂解酶氨基酸序列为SEQNO.2 序列所示，融合裂解酶氨基酸序列为SEQ NO.3所示。
2.权利要求1所述的一种从菌体外直接杀灭大肠杆菌的融合裂解酶构建方法，包括以下步骤：
1）用PCR的方法克隆出把大肠杆菌素的转运片段，连载的T-载体上，构建成重组质粒pUC-colicin；
2）用PCR的方法克隆出把噬菌体裂解酶的基因，连载的pUC-colicin，的大肠杆菌素的转运片段的下游，构建成重组质粒pUC-lysis
3）用内切酶把融合的大肠杆菌素的转运片段与噬菌体裂解酶的基因切下，并回收；把回收产物连接到原核表达载体pET-28上，构建成重组原核表达载体pET-lysis
4）把pET-lysis转化到大肠杆菌中，IPTG诱导表达融合裂解酶，并纯化。
CN201611202035.9A 2016-12-23 2016-12-23 一种用于裂解大肠杆菌的融合裂解酶 Expired - Fee Related CN107033246B (zh)

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CN112501189A (zh) * 2020-12-30 2021-03-16 吉林大学 一种能杀死马链球菌马亚种的裂解酶及其医用用途

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CN112501189A (zh) * 2020-12-30 2021-03-16 吉林大学 一种能杀死马链球菌马亚种的裂解酶及其医用用途

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