CN111349176B - 一种细菌素pzj5杂合肽c-p1及其应用 - Google Patents
一种细菌素pzj5杂合肽c-p1及其应用 Download PDFInfo
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- CN111349176B CN111349176B CN202010097201.3A CN202010097201A CN111349176B CN 111349176 B CN111349176 B CN 111349176B CN 202010097201 A CN202010097201 A CN 202010097201A CN 111349176 B CN111349176 B CN 111349176B
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- antibacterial
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Abstract
本发明公开了一种细菌素PZJ5杂合肽C‑P1，其氨基酸序列为：VKWKLFKKIKTKQQFLIKAQTQLF KVF。实验结果表明C‑P1显示出比母肽PZJ5更高的抗菌活性，并且没有溶血活性；采用扫描电镜和透射电镜研究了杂合肽C‑P1对大肠杆菌微观结构的影响，结果表明其抗菌机理与PZJ5相似，通过破坏细菌表面结构并导致内容物泄露，由于Cecropin A的N‑末端α‑螺旋片段与PZJ5的核心螺旋片段的协同作用，杂合肽C‑P1显示出优异的抗菌性质，其通过细胞表面和内部结构的破坏，从而导致细菌死亡。同时还观察到C‑P1与苍山籽精油对沙门氏菌显示出较强的协同作用。
Description
技术领域
本发明属食品科学和生物技术领域，特别是一种食品防腐剂。
背景技术
由化学防腐剂引起的食品安全风险是公众普遍关注的问题。一些抗微生物肽作为食品工业领域中的天然防腐剂逐渐引起关注。抗菌肽是一种短肽，其特征在于广谱的抗微生物活性。一些抗菌肽热稳定性好，对靶细胞无毒，同时能杀死微生物，可作为天然防腐剂的绝佳选择。
从乳酸菌中分离提取的细菌素PZJ5是由22个氨基酸残基组成的α螺旋肽，对大部分革兰氏阳性菌和革兰氏阴性菌都有较高的活性，无毒且具有良好的热稳定性。然而，它对一部分细胞的抗菌活性较低、在非酸性条件下无抑菌效果，这极大地限制了其在食品工业中的实际应用。本实验通过分子生物学和生物信息学方法对PZJ5进行肽序列的改造，获得抗菌活性更高、无细胞毒性且更适用于生产的新型杂合肽，使之能作为一种优良的天然防腐剂，更好地应用于食品工业。
发明内容
为了克服现有技术中的上述缺陷，本发明提供了一种细菌素PZJ5杂合肽 C-P1，实验证明其具有优异的抗菌性质，可通过细胞表面和内部结构的破坏，从而导致细菌死亡。另外，C-P1对绵羊血细胞没有显示出溶血活性。本发明的新型杂合肽C-P1可作为食品防腐剂。
本发明的第一个目的是提供一种细菌素PZJ5杂合肽C-P1，其特征在于：所述杂合肽的氨基酸序列为：VKWKLFKKIKTKQQFLIKAQTQLFKVF。
杂合肽C-P1通过将Cecropin A的具有两亲性的N端螺旋片段(1-8位氨基酸)与PZJ5的N-末端核心螺旋(1-18位氨基酸)连接并在杂合片段的N-末端添加缬氨酸(Val)以增加半衰期。对五种不同指示菌的抗菌活性实验表明，C-P1 的抗菌活性显著 高于亲本肽P的表达。C-P1的MIC范围为0.78至78.27μg/mL，而肽PZJ5的MIC范围为21至167μg/mL。当C-P1浓度为195.65μg/mL时的溶血率为0.43％，远低于50％。此时的浓度比C-P1的MIC高2.5-250倍。这些结果表明，杂合肽C-P1对红细胞的通透性几乎没有影响，具有较高的安全性。
本发明的第二个目的是提供一种食品防腐剂，其特征在于：所述食品防腐剂包含细菌素PZJ5杂合肽，杂合肽的氨基酸序列为： VKWKLFKKIKTKQQFLIKAQTQLFKVF。
进一步地，所述食品防腐剂还包括山苍籽精油。为进一步提高杂合肽的抗菌功效，C-P1与山苍籽精油组合进行协同作用的测试。结果表明，杂合肽C-P1与山苍籽精油对大肠杆菌的FIC指数为1，故具有叠加抑菌作用，对沙门氏菌的 FIC指数为0.138，存在较强的协同抑菌作用。
本发明以细菌素PZJ5为蓝本，通过连接不同抗菌肽片段，设计并合成了5 种杂合肽(C-P1、C-P2、P-M1、P-M2、P-M3)，结果表明C-P1显示出比母肽 PZJ5更高的抗菌活性，并且没有溶血活性；采用扫描电镜和透射电镜研究了杂合肽C-P1对大肠杆菌微观结构的影响，结果表明其抗菌机理与PZJ5相似，通过破坏细菌表面结构并导致内容物泄露，由于Cecropin A的N-末端α-螺旋片段与PZJ5的核心螺旋片段的协同作用，杂合肽C-P1显示出优异的抗菌性质，其通过细胞表面和内部结构的破坏，从而导致细菌死亡。同时还观察到C-P1与苍山籽精油对沙门氏菌显示出较强的协同作用。
附图说明
图1：抗菌肽疏水性和亲水性残基在肽螺旋区域的分布示意图。其中灰色圆圈表示两亲性中的亲水区域，黑色圆圈表示两亲性中的疏水区域，白色圆圈表示两亲性中的其他区域。
图2：扫描电镜与透射电镜图像，其中a：扫描电镜下未处理的大肠杆菌；b：扫描电镜下C-P在MIC下处理4h的大肠杆菌；c：扫描电镜下PZJ5-5在MIC 下处理4h的大肠杆菌；d：透射电镜下未处理的大肠杆菌；e：透射电镜下C-P 在MIC下处理4h的大肠杆菌；f：透射电镜下PZJ5-5在MIC下处理4h的大肠杆菌。
图3：用C-P1处理的细菌荧光显微镜图像。A：光学显微镜下未处理的大肠杆菌； b：荧光显微镜下未处理的大肠杆菌；c：荧光显微镜下C-P在MIC下处理4h的大肠杆菌；d：光学显微镜下未处理的沙门氏菌；e：荧光显微镜下未处理的沙门氏菌；f：荧光显微镜下C-P在MIC下处理4h的沙门氏菌。
图4：用PZJ5-5处理的细菌荧光显微镜图像。a：光学显微镜下未处理的铜绿假单胞菌；b：荧光显微镜下未处理的铜绿假单胞菌；c：荧光显微镜下PZJ5在MIC下处理4h铜绿假单胞菌；d：荧光显微镜下PZJ5-5在MIC下处理4h铜绿假单胞菌。
具体实施方式
材料
菌株：大肠杆菌(Escherichia coli)CGMCC 1.12883，铜绿假单胞菌(Pseudomonas aeruginosa)CGMCC 1.15148，粪肠球菌(Enterococcus faecalis) CGMCC1.15424，沙门氏菌(Salmonella sp.)CGMCC 1.755，单增李斯特菌(Listeriamonocytogenes)CGMCC 1.10753均购自中国普通微生物菌种保藏管理中心。
实施例1：新型肽的设计，合成和结构参数分析
利用ProtParam软件在线计算和分析新型肽的主要结构参数(分子质量、等电点、正电荷数、不稳定系数、脂肪系数、GRAVY)。通过DSC方法预测多肽的螺旋结构，并利用ANTHEPRO蛋白质序列软件进行亲水性疏水性分析。设计的多肽由上海吉尔生化有限公司合成并纯化，将多肽溶解于适量蒸馏水，-20℃保存。
本发明以PZJ5为蓝本设计了一系列杂合肽及突变衍生肽。C-P1是通过将Cecropin A的具有两亲性的N端螺旋片段(1-8位氨基酸)与PZJ5的N-末端核心螺旋(1-18位氨基酸)连接并在杂合片段的N-末端添加缬氨酸(Val)以增加半衰期。与其相似，C-P2是将Cecropin A 1-8位氨基酸与PZJ5 3-18位氨基酸拼接杂合；P-M1是将PZJ5 3-18位氨基酸与Magainin 2 1-12位氨基酸连接；P-M2 是将PZJ5 1-18位氨基酸与Magainin 2 1-12位氨基酸连接并在N-末端添加缬氨酸；P-M3是在P-M2基础上用缬氨酸替换第8位丝氨酸。PZJ5-1是PZJ5的16 个残基组成的内肽段，保留了PZJ5的整个α螺旋区。截取PZJ5的N末端，并用赖氨酸取代2位的苏氨酸，得到PZJ5-2。为了提高多肽的两亲性，我们以PZJ5-1 为基础设计了包含1-4个取代残基的类似物PZJ5-3、PZJ5-4、PZJ5-5和PZJ5-6。其中活性最高的PZJ5-5进行C末端酰胺化，得到PZJ5-7。抗菌肽的序列和理化性质如表1所示，疏水性和亲水性残基在肽螺旋区域的分布如图1所示。
表1抗菌肽序列及理化性质
实施例2：最低抑菌浓度(MIC)的测定和溶血活性测定
通过微量肉汤稀释法测定最低抑菌浓度(Minimal Inhibitory Concentrations，MIC)。将夜间培养的细菌细胞在相应液体培养基中稀释至105CFU/mL，96孔微量培养板中加入98μL稀释后的指示菌悬液和2μL抗菌肽连续稀释液，混合均匀，于37℃孵育16h。用酶标仪测定OD600，以判断指示菌株的生长情况。以含有指示菌的培养基为阳性对照，纯培养基为阴性对照。每组实验一式三份进行。
通过测量绵羊红细胞的溶血速率来评估肽的溶血活性。将新鲜绵羊红细胞离心15min，重悬于预先冷却的10mM磷酸盐缓冲盐水(PBS，pH＝7.4)。稀释至 5％悬浮液并等体积加入到肽的连续稀释液中，37℃下孵育1h。将悬浮液离心，并将上清液依次加入96孔微量培养板中。使用酶标仪测量542nm处OD值。以含有绵羊红细胞的PBS作阴性对照，含有绵羊红细胞的1％(v/v)Triton X-100 作阳性对照。所有实验一式三份进行。溶血率计算如下：
溶血率(％)＝(A1-A2)/(A3-A2)*100％
其中A1是肽处理组的OD值，A2是阴性对照组的OD值，A3是阳性对照组的OD值。
溶血率<50％，则为无溶血活性；溶血率>50％，则为有溶血活性，且溶血率越高，则溶血活性越强。
抗菌肽对五种不同指示菌的抗菌活性(表2)表明，C-P1的抗菌活性显著 高于亲本肽P的表达。C-P1的MIC范围为0.78至78.27μg/mL，而肽PZJ5的 MIC范围为21至167μg/mL。当C-P1浓度为195.65μg/mL时的溶血率为0.43％，远低于50％。此时的浓度比C-P1的MIC高2.5-250倍。这些结果表明，杂合肽C-P1对红细胞的通透性几乎没有影响，具有较高的安全性。如表2所示， PZJ5-5也表现出抗菌活性且与母肽PZJ5相当。尤其对铜绿假单胞菌，PZJ5-5表现出更高的抗菌活性。相较于PZJ5-5，PZJ5-7抗菌活性显著降低甚至丧失。此外，杂合肽CA-P1，P-M1，P-M2和P-M3以及衍生肽PZJ5-1、PZJ5-2、PZJ5-3、 PZJ5-4和PZJ5-6没有抗菌活性(结果未显示)。
表2抗菌肽对五种不同指示菌的抗菌活性
a)“—”表示无抗菌活性
实施例3：扫描电子显微镜(SEM)和透射电子显微镜(TEM)观察
指数期的大肠杆菌菌悬液中加入终浓度1×MIC抗菌肽于37℃温育4h， 2000g离心10min。沉淀用戊二醛固定后，PBS漂洗3次，并用锇酸再固定。再用PBS漂洗3次，经乙醇梯度脱水后，干燥、镀膜，使用扫描电子显微镜(scanning electron microscopy，SEM)观察。用纯丙酮处理脱水后菌液20min，用包埋剂与丙酮的混合液(V/V＝1/1和3/1)分别处理样品1h和3h，纯包埋剂处理样品过夜。将经过渗透处理的样品在70℃包埋过夜后切片，经柠檬酸铅溶液和醋酸双氧铀50％乙醇饱和溶液各染色5-10min，使用透射电子显微镜(transmissionelectron microscopy，TEM)观察。
将对数期的菌悬液离心后收集沉淀，PBS漂洗三次后重悬于PBS。抗菌肽(终浓度1×MIC)分别添加到菌悬液中孵育4h，加入PI染色剂(2.5μg/mL)于黑暗中染色30min。实验以正常的对数期细菌细胞作阴性对照组。取10μL染色后的菌悬液涂片并置于荧光显微镜下观察。
扫描电子显微镜(SEM)能够直接观察细菌表面形态的变化，而透射电子显微镜(TEM)可以直接观察细菌内部物质结构的变化。在扫描电镜下(图2，b 和c)，肽处理后的大肠杆菌O104与未处理的细胞(图2，a)相比菌体边缘不整，表面变粗糙，且细胞有皱缩现象，有杂质附着。通过透射电镜高倍放大观察到肽处理后的大肠杆菌(图2，e和f)菌体边缘破裂、空泡化、胞壁缺陷，而未处理的细胞(图2，d)则显示出菌体内容物饱满、紧密、无缺陷。这些结果表明，C-P1和PZJ5-5都是通过大肠杆菌细胞壁破裂或者孔洞的形成，导致其内容物泄漏，细胞代谢无法正常进行，从而最终导致细菌细胞的死亡。
荧光染料PI是一种核染色试剂，可以穿过受损的细胞膜进入细胞使细胞核染色。因此，PI可被用于检测细胞死亡或者检测多肽渗透细菌膜的能力。本研究中，大量抗菌肽C-P1处理后的细胞在荧光显微镜下呈现出大片红色荧光(图 3，c和f)，而正常生长的细胞几乎未被染色(图3，b和e)。因此，可确定抗菌肽C-P1对细菌的抑菌模式为杀菌。经PZJ5-5处理过的铜绿假单胞菌(图4，d) 荧光强度强于经PZJ5处理过的铜绿假单胞菌(图4，c)荧光强度，这与PZJ5-5 对铜绿假单胞菌抗菌活性高于PZJ5的研究结果一致。
实施例4：协同作用分析
本实验采用棋盘滴定法对抗菌肽C-P1和山苍籽精油的协同作用进行研究。将抗菌肽C-P1和山苍籽精油以一系列浓度混合(范围为1/16MIC至3MIC)。所有实验一式三份进行。分数抑制浓度(fractional inhibitory concentration，FIC) 指数计算方程式：
FIC指数＝FICA+FICB＝A/MICA+B/MICB
其中A和B是具有抗菌活性组别中物质A和物质B的加样量；MICA和 MICB是物质A和物质B的MIC；FICA和FICB是物质A和物质B的FIC。
FIC指数判断：<0.5协同作用；0.5至1.0叠加作用；1.0到4.0无作用；>4.0拮抗作用。
为进一步提高杂合肽的抗菌功效，C-P1与山苍籽精油组合进行协同作用的测试。结果表面，杂合肽C-P1与山苍籽精油对大肠杆菌O104的FIC指数为1，故具有叠加抑菌作用，对沙门氏菌的FIC指数为0.138，故存在较强的协同抑菌作用。
序列表
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Val Lys Thr Lys Gln Gln Phe Leu Ile Lys Ala Gln Thr Gln Leu Phe
1 5 10 15
Lys Val Phe Gly Ile Gly Lys Phe Leu His Val Ala Lys Lys Phe
20 25 30
<210> 6
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Lys Gln Gln Phe Leu Ile Lys Ala Gln Thr Gln Leu Phe Lys Val Phe
1 5 10 15
<210> 7
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Lys Lys Lys Gln Gln Phe Leu Ile Lys Ala Gln Thr Gln Leu Phe Lys
1 5 10 15
Val Phe
<210> 8
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Ala Gln Gln Phe Leu Ile Lys Ala Gln Thr Gln Leu Phe Lys Val Phe
1 5 10 15
<210> 9
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Ala Leu Gln Phe Leu Ile Lys Ala Leu Thr Gln Leu Phe Lys Val Phe
1 5 10 15
<210> 10
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 10
Ala Gln Gln Phe Leu Lys Lys Ala Gln Thr Gln Leu Lys Lys Val Phe
1 5 10 15
<210> 11
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
Ala Ile Gln Phe Leu Gln Lys Ala Phe Thr Gln Leu Gln Lys Val Phe
1 5 10 15
<210> 12
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 12
Ala Gln Gln Phe Leu Lys Lys Ala Gln Thr Gln Leu Lys Lys Val Phe
1 5 10 15
Claims (3)
1.一种细菌素PZJ5杂合肽C-P1，其特征在于：所述杂合肽的氨基酸序列为：VKWKLFKKIKTKQQFLIKAQTQLFKVF。
2.一种食品防腐剂，其特征在于：所述食品防腐剂包含细菌素PZJ5杂合肽，杂合肽的氨基酸序列为：VKWKLFKKIKTKQQFLIKAQTQLFKVF。
3.如权利要求2所述的食品防腐剂，其特征在于，所述食品防腐剂还包括山苍籽精油。
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Citations (3)
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|---|---|---|---|---|
| CN101323644A (zh) * | 2008-03-21 | 2008-12-17 | 瑞普（保定）生物药业有限公司 | 重组cecA-mil杂合基因抗菌肽 |
| WO2010061203A1 (en) * | 2008-11-28 | 2010-06-03 | The Secretary Of State For Defence | Biocidal fusion peptide comprising ll-37 |
| CN102199196A (zh) * | 2010-09-03 | 2011-09-28 | 青岛康地恩药业有限公司 | 一种基因工程抗菌肽及其制备方法和应用 |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101323644A (zh) * | 2008-03-21 | 2008-12-17 | 瑞普（保定）生物药业有限公司 | 重组cecA-mil杂合基因抗菌肽 |
| WO2010061203A1 (en) * | 2008-11-28 | 2010-06-03 | The Secretary Of State For Defence | Biocidal fusion peptide comprising ll-37 |
| CN102199196A (zh) * | 2010-09-03 | 2011-09-28 | 青岛康地恩药业有限公司 | 一种基因工程抗菌肽及其制备方法和应用 |
Non-Patent Citations (3)
| Title |
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| Novel Hybrid Peptide Cecropin A(1-8)-LL37(17-30) with Potential Antibacterial Activity;Xu-Biao Wei，et al;《International Journal of Molecular Sciences》;20160629;第17卷(第7期);第1页第1段、最后1段 * |
| 山苍籽及其精油研究利用现状分析;杨保刚 等;《四川食品与发酵》;20041218;第40卷(第4期);摘要、第12页右栏第3段 * |
| 新型植物乳杆菌细菌素PZJ5的分离纯化及特性研究;宋达峰;《中国博士学位论文全文数据库 基础科学辑》;20150115;摘要 * |
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