南京农业大学学报  2018, Vol. 41 Issue (5): 784-792   PDF    
http://dx.doi.org/10.7685/jnau.201804019
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文章信息

陆兆新, 孟凡强
LU Zhaoxin, MENG Fanqiang
植物乳杆菌素合成及其调控机制的研究进展
Research advance on regulatory mechanism of plantaricin synthesis in Lactobacillus plantarum
南京农业大学学报, 2018, 41(5): 784-792
Journal of Nanjing Agricultural University, 2018, 41(5): 784-792.
http://dx.doi.org/10.7685/jnau.201804019

文章历史

收稿日期: 2018-04-10
植物乳杆菌素合成及其调控机制的研究进展
陆兆新 , 孟凡强     
南京农业大学食品科技学院, 江苏 南京 210095
摘要:植物乳杆菌素(plantaricin)是由多个氨基酸组成的多肽类抗菌素。它是一类重要细菌素,具有种类多、抑菌谱广、不易产生耐药性、安全性高等优点,因此在食品、饲料和医药等领域有潜在应用价值。然而,因植物乳杆菌素产量低而影响了其在食品和医药中的应用。本文从植物乳杆菌素种类、群体感应系统及植物乳杆菌素基因簇等方面介绍植物乳杆菌素诱导及调控的最新研究进展。
关键词植物乳杆菌素   群体感应系统   诱导方式   调控机制   
Research advance on regulatory mechanism of plantaricin synthesis in Lactobacillus plantarum
LU Zhaoxin , MENG Fanqiang    
College of Food Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
Abstract: Plantaricin is a polypeptide bacteriocin composed of amino acids. It is a kind of important bacteriocin, with various types, broad anti-bacteria spectrum, tolerance to drug, and high safety. Therefore, it has a potential application in the fields of food, feed and medicine. However, its application in food and medicine is restricted due to the low yield. In this paper, the latest research on regulatory mechanism of plantaricin synthesis is introduced from the aspects of plantaricin species, quorum-sensing system and plantaricin gene clusters.
Keywords: plantaricin    quorum-sensing system    inducible mode    regulatory mechanism   

细菌素是细菌生长过程中产生的具有抗菌作用的多肽类物质及其衍生物。细菌素具有种类多样、不易产生耐药性和安全性高的特点, 它既可以由核糖体控制合成, 也可以通过非核糖体途径(NRPS\PKS)合成。芽胞杆菌属(Bacillus)、链霉菌属(Streptomyces)和乳酸菌均可以产生细菌素。其中乳酸菌是公认安全的微生物, 在乳制品、蔬菜、水果、肉类等食品的发酵与防腐过程中发挥着重要作用。乳酸菌细菌素对多种食源性致病菌如单增李斯特菌(Listeria monocytogenes)、金黄色葡萄球菌(Staphylococcus aureus)、沙门氏菌(Salmonella)、大肠杆菌(Escherichia coli)、空肠弯曲菌(Campylobacter jejuni)、副溶血性弧菌(Vibrio parahemolyticus)、志贺氏菌(Shigella)等, 具有良好的抑制效果[1]。乳酸菌细菌素可以控制食源性致病菌传播, 减轻食源性致病菌危害[2-3], 因此具有替代化学防腐剂的潜力。某些细菌素对致粮食腐败相关真菌如黄曲霉(Aspergillus flavus)、赭曲霉(Aspergillus ochraceus)和镰刀菌(Fusarium)等具有显著的抑制效果[4], 可明显降低粮食贮藏期间因腐败变质造成的损失, 具有极大的应用价值[5]。因此, 细菌素的使用可以减少食品加工和粮食贮藏过程中化学防腐剂的应用, 也可以减少饲料中抗生素的残留。

目前限制细菌素大规模应用的主要原因是细菌素产量太低, 无法满足大规模生产要求。唯一被批准用作食品添加剂的乳酸链球菌素(nisin)对食品腐败菌和部分致病的革兰氏阳性菌具有很好的抑制效果, 其最高发酵活力仅为6 380 IU · mL-1[6]。因此, 阐明植物细菌素合成调控机制, 为在分子水平上改造细菌素合成途径, 提高细菌素产量提供理论依据。

1 植物乳杆菌素的种类及抑菌活性

植物乳杆菌素(plantaricin)产自植物乳杆菌(Lactobacillus), 是具有细胞膜透化作用的阳离子肽, 长度一般在25~60个氨基酸残基。Pal等[7]和Cho等[8]从植物乳杆菌中分离出植物乳杆菌素EF和JK, 并对其抑菌活性进行研究, 发现其对李斯特菌(Listeria)、微球菌(Micrococcus)、肠球菌(Enterococcus)、乳球菌(Lactococcus)等具有抑菌活性。研究人员从植物乳杆菌纯化鉴定出KL-1Y、ⅡA-1A5、ZJ008、ZJ5、LD1、A-1、Y等新型植物乳杆菌素, 并对其抑菌谱进行初步研究。如表 1所示:大多数植物乳杆菌素对近缘乳酸菌如植物乳杆菌(Lactobacillus)、明串珠菌(Leuconostoc)、片球菌(Pediococcus)、乳球菌(Lactococcus)等的抑制效果较好。

表 1 植物乳杆菌素种类及其抑菌活性 Table 1 Species and their antibacterial activity of plantaricin
植物乳杆菌素
Plantaricin
产生菌
Strain
抑菌谱
Antibacterial spectrum
参考文献
References
SIK-83 SIK-83 乳杆菌、明串珠菌、片球菌等Lactobacillus, Leuconostoc, Pediococcus, et al [9]
BN BN 梭菌、李斯特菌Clostridium, Listeria [10]
LC74 LC74 乳杆菌、明串珠菌Lactobacillus, Leuconostoc [11]
S LPCO10 乳杆菌Lactobacillus [12]
SA6 SA6 乳杆菌、明串珠菌、李斯特菌Lactobacillus, Leuconostoc, Listeria [13]
C LL441 乳杆菌、链球菌、梭菌等Lactobacillus, Streptococcus, Clostridium, et al [14]
UG1 UG1 李斯特菌、芽胞杆菌、梭菌等Listeria, Bacillus, Clostridium, et al [15]
KW30 KW30 乳杆菌、明串珠菌Lactobacillus, Leuconostoc [16]
A C11, WCFS1 片球菌、乳杆菌Pediococcus, Lactobacillus [17]
D BFE 905 李斯特菌Listeria [18]
423 423 李斯特菌、葡萄球菌、片球菌等Listeria, Staphylococcus, Pediococcus, et al [19]
NA NA 李斯特菌、乳杆菌Listeria, Lactobacillus [20]
LP84 NCIM 2084 芽胞杆菌、大肠杆菌、葡萄球菌等Bacillus, Escherichia coli, Staphylococcus, et al [21]
E、F、J、K C11, WCFS1 片球菌、乳杆菌Pediococcus, Lactobacillus [17]
1^25α、1^25β TMW1^25 乳杆菌Lactobacillus [22]
35d 35d 李斯特菌Listeria [23]
C19 C19 李斯特菌Listeria [24]
W LMG 2379 乳杆菌Lactobacillus [25]
NC8α、NC8β NC8 乳杆菌Lactobacillus [26]
TF711 TF711 芽胞杆菌、梭菌、克雷伯菌等Bacillus, Clostridium, Klebsiella, et al [27]
OL15 OL15 乳杆菌、乳球菌、丙酸杆菌Lactobacillus, Lactococcus, Propionibacterium [28]
L-1 L-1 李斯特菌Listeria [29]
149 NRIC 149 葡萄球菌、李斯特菌Staphylococcus, Listeria [30]
LR14 LR/14 藤黄微球菌Micrococcus luteus [31]
ST8SH ST8SH 乳杆菌、李斯特菌、肠球菌Lactobacillus, Listeria, Enterococcus [32]
ASM1 A-1 明串珠菌、乳杆菌、肠球菌等Leuconostoc, Lactobacillus, Enterococcus, et al [33]
MG KLDS1^0391 沙门氏菌Salmonella [34]
163 163 葡萄球菌、李斯特菌、大肠杆菌等Staphylococcus, Listeria, E. coli, et al [35]
BM-1 BM-1 李斯特菌、葡萄球菌、沙门氏菌等Listeria, Staphylococcus, Salmonella, et al [36]
Y 510 李斯特菌、乳杆菌、魏斯氏菌等Listeria, Lactobacillus, Weissella, et al [37]
ZJ008 ZJ008 葡萄球菌、假单胞菌、大肠杆菌等Staphylococcus, Pseudomonas, E. coli, et al [38]
ZJ5 ZJ5 葡萄球菌、假单胞菌、芽胞杆菌等Staphylococcus, Pseudomonas, Bacillus, et al [39]
LD1 LD1 乳杆菌、葡萄球菌、沙门氏菌等Lactobacillus, Staphylococcus, Salmonella, et al [40]
IIA-1A5 IIA-1A5 葡萄球菌Staphylococcus [41]
163-1 163 葡萄球菌、李斯特菌、大肠杆菌等Staphylococcus, Listeria, E. coli, et al [42]
KL-1Y KL-1 沙门氏菌、假单胞菌、大肠杆菌等Salmonella, Pseudomonas, E. coli, et al [43]
JLA-9 JLA-9 芽胞杆菌、梭菌、沙门氏菌等Bacillus, Clostridium, Salmonella, et al [44]
Q7 Q7 假单胞菌、李斯特菌、大肠杆菌等Pseudomonas, Listeria, E. coli, et al [45]
K25 K25 芽胞杆菌、李斯特菌、葡萄球菌等Bacillus, Listeria, Staphylococcus, et al [46]
PLN1 163 微球菌、葡萄球菌、李斯特菌等Micrococcus, Staphylococcus, Listeria, et al [47]
JY22 JY22 芽胞杆菌Bacillus [48]
DL3 DL3 铜绿假单胞菌Pseudomonas aeruginosa [49]
SLG1 SLG1 芽胞杆菌、李斯特菌、酿酒酵母等Bacillus, Listeria, Saccharomyces cerevisiae, et al [50]

另外植物乳杆菌素BN、C、TF711、JLA-9对梭菌(Clostridium)具有抑制效果。植物乳杆菌素BN、SA6、UG1、D、423、NA、35d、C19、L-1、ST8SH、163、BM-1、K25等对李斯特菌(Listeria)具有较好的抑制作用; 植物乳杆菌素MG、BM-1、LD1、KL-1Y、JLA-9对沙门氏菌(Salmonella)有抑制作用; 植物乳杆菌素423、LP84、149、163、BM-1、ZJ008、ZJ5、LD1、IIA-1A5、163-1、K25、PLN1对葡萄球菌(Staphylococcus)具有抑制效果。植物乳杆菌素对于抑制耐药性的金黄色葡萄球菌和表皮葡萄球菌具有潜在的应用价值。对于降低食源性致病菌(李斯特菌、沙门氏菌等)的污染具有良好的效果。除此之外, 部分植物乳杆菌素还对芽胞杆菌(Bacillus)[21, 27]、大肠杆菌(E.coli)[21, 35]、微球菌(Micrococcus)[31]、假单胞菌(Pseudomonas)[45]等具有明显的抑制作用。许多研究人员对细菌素的作用方式和作用机制进行了总结, 并对影响细菌素抑菌效果的因素, 如电荷、疏水性结构、极性角等也进行了分析[51-53]

2 乳酸菌群体感应诱导合成细菌素

群体感应(quorum sensing, QS)是细菌产生、分泌并检测信号分子作出特殊反应调控细菌生长的信息交流过程。细菌通过感知环境中特殊的信号分子来识别种群密度, 当种群密度达到较高水平时, 环境中信号分子数量逐步提高至一定水平, 从而激活信号通路调控细菌基因表达并做出相应反应。1997年Saucierd在栖鱼肉杆菌(Carnobacterium piscicola LV17)中首先发现了乳酸菌的群体感应现象[54]。随后研究人员在多种乳酸菌中均发现有群体感应现象, 并且证明群体感应与细菌素合成密切相关。根据信号分子和受体蛋白不同将群体感应分为4类:第1类是革兰氏阴性菌中的N-酰基高丝氨酸内酯类(AHL)介导的LuxI/R群体感应系统; 第2类是革兰氏阳性菌中的寡肽类介导的群体感应系统; 第3类是AI-2介导的LuxS/AI-2系统; 第4类是AI-3/肾上腺素/去甲肾上腺素系统。乳酸菌中的群体感应系统属于第2类和第3类[55]

AI-2是一种呋喃酰硼酸二酯类化合物, 与细菌种群间的信息交流有关。有研究表明AI-2与植物乳杆菌素的合成有关; 在植物乳杆菌液体培养基中加入人工合成的AI-2分子, 但细菌的生长不受影响, 细菌素的产量明显提高, 植物乳杆菌素合成基因plnEF的表达量提高了1.89倍。张腾等[56]将植物乳杆菌HE-1与多种细菌共培养, 结果表明抑菌物质的产生与AI-2信号分子在时间和数量上存在相关性。当其与乳酸乳球菌MG1363共培养时, 植物乳杆菌素合成量可高达2 560 BU · mL-1[57]。相关研究表明,在植物乳杆菌KLDS1.0391生长过程中会分泌信号分子AI-2, 当AI-2达到一定浓度后, 能够激活编码细菌素相关基因表达[58]。有报道称不产细菌素的乳酸菌通过与其他菌株共培养后可能会诱导产生抗菌物质, 并且AI-2可能是诱导物。但也有报道称共培养后本来产细菌素的菌株, 其产细菌素能力反而受到抑制[59]。此外, 诱导菌的种类还与乳酸菌菌株性状有关, 具有高度的菌株特异性。诱导菌可以是近缘乳酸菌也可以是远缘其他属菌株; 可以是活菌, 也可以是温和热处理的细胞或者高压蒸汽处理的细胞[60]

植物乳杆菌中另外一种调控系统是寡肽类信号分子(auto-inducing peptide, AIP)介导的群体感应系统(plnABCD)。不同植物乳杆菌合成的细菌素存在差异, 其控制合成植物乳杆菌素的基因簇(pln)也不相同。Saenz等[61]和Diep等[62]对植物乳杆菌WCFS1、ST-Ⅲ、JDM1、C11、J51、NC8、J23等的pln基因簇进行了总结分析,如图 1所示。

图 1 主要植物乳杆菌中pln基因簇结构[47, 61, 63-64, 66] Figure 1 pln gene cluster structure in Lactobacillus plantarum[47, 61, 63-64, 66]

在植物乳杆菌C11、WCFS1、J51、YM-4-3中[61], 其pln基因簇全长为18~19 kb, 分为5个操纵子:plnABCDplnJKLRplnMNOPplnEFIplnGHSTUVW[63]plnJKLRplnEFI编码2组具有协同作用的Ⅱa类细菌素(植物乳杆菌素EF和JK)以及相关的免疫蛋白(PlnI和PlnL); plnGHSTUVW编码转运蛋白及其辅助蛋白, 参与细菌素的运输、分泌和加工; plnMNOP功能未知; plnABCD编码的是群体感应调控系统[61], 该操纵子既能激活自身转录也能激活另外4个操纵子转录。plnA编码自诱导肽(AIP), plnB编码组氨酸激酶(HPK), plnCplnD编码反应调节因子[8]。其中plnC编码激活基因簇转录蛋白, plnD编码抑制基因簇转录蛋白。植物乳杆菌J51的植物乳杆菌素基因簇结构与植物乳杆菌C11不同, 但其调控基因相同,均为plnABCD, 所以它们具有相同的调控方式。

在植物乳杆菌NC8、J23、LZ206、PCS20中, 其植物乳杆菌素基因簇总体结构与植物乳杆菌C11、WCFS1相似, 但是调控系统结构不一致, 其三组分调控系统为plnNC 8IF-HK-plnD [61-62]。其中plnNC8IF产生自诱导肽, plnNC8HK编码产生组氨酸激酶。plnD编码反应调节因子, 其与植物乳杆菌C11中的plnD具有高度同源性。在植物乳杆菌JDM1、UL4、163、LPT70/3、LB6、5-2、ZJ316中[8, 47, 64-65], 虽然它们控制合成植物乳杆菌素的基因簇结构不同, 但是它们的三组分信号转导系统(plnIF-HK-D)具有与植物乳杆菌NC8、J23相似的结构, 调控方式也基本相同。

此外, 我们通过对plnABCD关联基因分析(https://string-db.org/)发现, plnABCD表达还可能与其他群体感应系统如lamBDCApltAKRrrp8-hpk9有一定关系(图 2)。群体感应lamBDCA系统是通过调节胞外多糖合成来控制细胞的黏着能力和生物膜的形成。因此推测该系统在植物乳杆菌与人胃肠道黏着、定殖过程中扮演重要角色[67]hpk9基因编码群体感应系统中的组氨酸激酶, rrp8基因编码反应调节因子, 它们也可能是一种群体感应系统调控系统。所以, 植物乳杆菌素的合成不仅与pln基因簇和AI-2信号分子相关, 还可能与其他群体感应系统或者调控基因有关。

图 2 与植物乳杆菌素调控基因plnABCD相关的基因网络 Figure 2 Gene network associated with the plantaricin regulatory gene plnABCD
3 plnABCD编码的植物乳杆菌素合成调控系统

植物乳杆菌的调控方式如图 3所示, 其首先在核糖体中合成AIP的前体肽(pre-AIP)。前体肽在向外运输过程中, 经过特殊的转录后修饰与加工, 形成内酯环、硫醇内酯环、羊毛硫氨酸等不同结构, 成为具有活性的AIP。AIP通过ABC转运系统(ABC-transporter)或其他膜通道蛋白分泌到细胞外行使功能。AIP分子浓度随细菌密度增大而增加, 达到一定阈值时, AIP激活双组分信号转导系统(plnABCDplnNC8IF-HK-plnD)中的组氨酸激酶(PlnB), 进而激活反应调节因子(PlnC、PlnD)的表达, 最终控制细菌簇中相关基因的表达。前体植物乳杆菌素(pre-plantaricin)通过ABC转运系统转运到细胞外, 并切掉信号肽形成具有抑菌活性的成熟肽。此外细胞膜上还有植物乳杆菌素相关受体(immuno-protein), 能够使植物乳杆菌具有免疫植物乳杆菌素的能力[66, 68]。Maldonado-Barragan等[69]通过敲除植物乳杆菌WCFS1的plnABCD基因和植物乳杆菌NC8的plnNC8IF-HK-D基因证明植物乳杆菌素产生与该基因簇相关。研究表明, 敲除plnB基因后植物乳杆菌L-XM1细菌素的产量降低, 并且无法检测到细菌素合成基因plnEF/JK的转录[70]

图 3 植物乳杆菌素群体感应系统调控方式[62] Figure 3 Quorum sensing system regulation mode of L.plantarum[62]

对AIP的结构研究[71]表明植物乳杆菌C11中AIP(PlnA)的N端为无规则卷曲结构, C端为α-螺旋结构(图 4)。N端区域可能是与组氨酸激酶(PlnB)结合的区域, C端区域疏水性较强, 可能是与细胞膜结合区域。组氨酸激酶PlnB由N端的传感区域, 中间的跨膜结构域和C端的激酶核心结构域组成[70], N端的传感区域能够感受环境中自诱导肽浓度, C端的激酶核心结构域具有保守的ATP结构域, 能够水解ATP使PlnC和PlnD磷酸化, 从而激活基因簇转录。Johnsborg等[72]通过软件预测, 结果显示PlnB具有6个跨膜区, 3号跨膜区没有穿过整个细胞膜又返回胞外。PlnB的N端或其他膜外部分具有PlnA结合位点(图 4)。随后Johnsborg等[73]利用定点突变技术改变PlnB氨基酸组成, 结果表明突变植物乳杆菌C11的PlnB中的D54A和S58A突变会导致植物乳杆菌素合成诱导效率下降, D54和S58突变可能在PlnA发挥诱导激活作用中起积极作用。

图 4 植物乳杆菌中PlnA(AIP)和PlnB(HPK)空间结构模型[70-73] Figure 4 Spatial structure model of PlnA(AIP)and PlnB(HPK)in L.plantarum[70-73] 图中PlnB的柱状图表示跨膜结构域, 椭圆部分具有组氨酸激酶活性。蓝色为酸性氨基酸, 橙色为碱性氨基酸。三角形位置的氨基酸替换为丙氨酸后, 降低对信号分子的敏感性。六边形位置的氨基酸替换为丙氨酸后, 组氨酸激酶活性升高。 The histogram in the figure is plnB, which represents the transmembrane domain; the elliptic part has histidine kinase activity. The blue is acidic amino acid, orange is basic amino acid. The activity of histidine kinase is reduced when the triangular position amino acid is replaced by alanine. The activity of histidine kinase increased when the amino acid substitution at the hexagonal position is replaced by alanine.

转录激活因子PlnC和转录抑制因子PlnD控制pln基因簇下游基因的转录, 所有pln基因簇中的启动子序列区域都含有与PlnC和PlnD结合的保守序列。该序列为直接重复序列, 例如在PlnA和NC8IF中的结合序列为ACGTTTA和TACGTTAAT, 在plnG启动子中的结合序列为GACATTTAT和TACGTTAAT, 在plnEF启动子的结合序列为GACGTTAAG和TACTTTTAT, 在plnJK启动子的结合序列为TACGTTAAA和TACGATAAC[74]。PlnC和PlnD以同型二聚体的形式结合相同的DNA序列以发挥调控功能。但是二者对启动子结合的强度不同, PlnC易与plnA启动子结合而与plnG启动子结合较差, PlnD与之相反。所以PlnC和PlnD虽然有很高的同源性和相同的结合序列, 但是它们对pln基因簇中启动子结合常数的差异构成了植物乳杆菌素生物合成调控的基础。因此, 对PlnD和PlnC进行定点突变, 调控其与启动子的结合效率, 对于提高细菌素合成有重要的应用价值。

综上所述, 植物乳杆菌素合成存在复杂的调控机制, 可能与群体感应系统中的种间信号分子AI-2相关, 也与植物乳杆菌素自身基因簇中的调控系统(AIP介导的群体感应系统)相关, 还可能与细胞中的其他群体感应系统相关。

4 展望

除群体感应相关系统之外, 植物乳杆菌素合成还可能与细菌的代谢过程相关。许多研究者通过改变培养基成分极大提高了细菌素的产量, 这表明在细胞密度不变的情况下, 植物乳杆菌素产量还能提升。目前关于培养基成分影响植物乳杆菌素合成的机制尚不清晰, 相关研究较少。我们可以通过转录组学技术, 分析植物乳杆菌在不同培养基、不同培养条件和不同生长时间段内mRNA的变化, 得到与植物乳杆菌素合成正相关和负相关的基因,再通过蛋白质组学技术在蛋白质层面上验证转录组学的结果。采用分子生物学手段敲除或者敲入基因达到调控植物乳杆菌素合成, 提高产量的目的。还可以通过代谢组学方法分析不同营养成分对植物乳杆菌素合成的影响, 及其代谢过程中代谢路径的改变情况及能量、氨基酸等分配的变化。修饰和改造植物乳杆菌素的诱导调控路径和代谢调控路径, 为大规模生产提供理论依据。

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