CN115054606B - 一种猪链球菌丝氨酸苏氨酸蛋白激酶抑制剂及其应用 - Google Patents
一种猪链球菌丝氨酸苏氨酸蛋白激酶抑制剂及其应用 Download PDFInfo
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Abstract
本发明公开了一种猪链球菌丝氨酸苏氨酸蛋白激酶抑制剂及其应用，属于医药技术领域。本发明的抑制剂K‑252a对丝氨酸苏氨酸蛋白激酶的酶活抑制率为66.3%，对丝氨酸苏氨酸蛋白激酶的酶活半抑制浓度为13.81 μM，其能够显著抑制猪链球菌的生长，可用于制备抗菌药物。
Description
技术领域
本发明属于医药技术领域，具体涉及一种猪链球菌丝氨酸苏氨酸蛋白激酶抑制剂及其在制备抗菌药物中的应用。
背景技术
开发新型抗菌药物是应对当前严峻耐药性形势的重要手段，针对细菌关键调控蛋白开展抑制剂筛选将为新型抗菌化合物筛选提供重要基础。在多种革兰氏阳性菌厚壁门的细菌中存在一种具有重要调控作用真核样丝氨酸苏氨酸蛋白激酶STK。已经有研究表明STK是结核分枝杆菌、假结核耶尔森菌和金黄色葡萄球菌等病原菌的重要毒力和代谢调控蛋白。在猪链球菌中，STK参与细菌生长、分裂、碳代谢、生物被膜形成等重要生理过程。由于STK在病原菌生理和致病过程中发挥重要作用，其被认为是一种潜在的抗菌药物靶标。
猪链球菌STK包含胞外结构域、跨膜结构域和胞内催化结构域，在特定条件下STK被激活，使得胞内催化结构域发生自磷酸化，之后通过其激酶活性使其底物蛋白的丝氨酸/苏氨酸位点发生磷酸化，发挥调控作用。我们的前期研究表明，当STK的自磷酸化位点突变后，STK的功能受到显著影响，表明可以通过抑制STK的自磷酸化来抑制STK的功能。基于此，可利用基于STK自磷酸化酶活测定的方法筛选STK的抑制剂。
发明内容
本发明目的在于提供一种猪链球菌丝氨酸苏氨酸蛋白激酶STK的抑制剂，本发明的目的还在于提供所述的抑制剂在制备抗菌药物中的应用。
本发明所筛选的抑制剂能够抑制猪链球菌丝氨酸苏氨酸蛋白激酶STK的活性，并抑制猪链球菌的生长。
本发明的目的通过下述技术方案实现：
一种猪链球菌丝氨酸苏氨酸蛋白激酶的抑制剂，其为结构式如下所示的化合物K-252a：
该化合物为(9S,10R,12R)-9,12-环氧-1H-二吲哚并[1,2,3-fg：3',2',1'-kl]吡咯并[3,Chemicalbook4-i][1,6]苯并重氮辛-10-羧酸,2,3,9,10,11,12-六氢-10-羟基-9-甲基-1-氧代甲酯，分子式为C27H21N3O5，分子量为467.47。
上述抑制剂在抗菌中的应用，所述的应用为非疾病治疗的目的。
上述抑制剂在制备抗菌药物中的应用。
所述的抗菌为抑制猪链球菌生长。
一种抗菌药物，包含上述抑制剂。
本发明的有益效果：本发明的丝氨酸苏氨酸蛋白激酶抑制剂对10μM STK的酶活抑制率为66.3％，其对STK的半抑制浓度为13.81μM，能够显著抑制猪链球菌的生长。
附图说明
图1：实施例1中的质粒构建模式图。其中图1(A)是pET28a载体图谱；图1(B)是STK表达质粒构建图。
图2：9种广谱激酶抑制剂staurosporine结构类似小分子对STK酶活的抑制作用。
图3：K-252a对STK酶活的半抑制浓度(IC50)测量结果。K-252a对STK酶活的IC50为13.81μM。
图4：K-252a对猪链球菌生的生长抑制作用。与对照相比，K-252a处理后猪链球菌SC19菌株生长受到明显抑制。
具体实施方式
以下实施例用于进一步说明本发明，但不应理解为对本发明的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。
若未特别指明，实施例中所用的技术手段为本领域技术人员所熟知的常规手段。
实施例1靶向猪链球菌丝氨酸苏氨酸蛋白激酶STK的抑制剂K-252a的筛选步骤：
1、猪链球菌丝氨酸苏氨酸蛋白激酶STK胞内结构域表达质粒的构建与蛋白纯化
将原核表达载体pET28a(图1A)酶切位点经NdeI与XhoI进行双酶切处理后，用1％琼脂糖凝胶电泳检测和DNA回收试剂盒回收，以猪链球菌SC19基因组(NZ_CP020863)为模板，以引物STK-F：CCCATATGATGATTCAAATCGGTAAGATCTTTGC和STK-R：CCCTCGAGTTGGGAGAGTTTCGGCAAG扩增stk的胞内结构域片段，用同源重组酶连接酶切载体和PCR片段，转化至大肠杆菌DH5α感受态中，37℃过夜培养，挑取单菌落进行PCR鉴定，挑取阳性克隆过夜培养后，利用质粒小提试剂盒提取质粒进行DNA测序，获得重组质粒pET28a-STK(图1B)。
将测序正确的重组质粒转化至大肠杆菌BL21(DE3)感受态中，将转化子细菌接种至LB液体养基，37℃下180rpm扩大培养，待菌液生长至OD600 nm为0.6-0.8之间时，加入1mMIPTG在18℃下180rpm摇床中培养16h，之后4℃下8000rpm离心10min收集菌体，将菌体重悬于磷酸盐缓冲液中，并用压力破碎仪破碎细菌，4℃下10000rpm离心15min去除细菌碎片，上清细菌裂解液使用镍柱进行亲和层析，根据280nm的吸收峰，收集样品，并进行SDS-PAGE验证，同时用超滤管对蛋白进行浓缩，获得纯化的STK。
2、基于酶活性抑制剂筛选
2.1在黑色平底96孔板中加入44μL酶活反应液，包含10mM MgCl2、10μM STK和pH7.0的激酶缓冲液(50mM HEPES，1mM DTT和0.01％Brij35)，之后每孔加入1μL DMSO溶解的浓度为10mM的9种与广谱性激酶抑制剂Staurosporine结构类似的小分子，小分子结构见表1，购自MedChemExpress，并设置加激酶的阳性对照与不加激酶的阴性对照，每个样品设置3个重复。
表1. 9种广谱激酶抑制剂Staurosporine结构类似小分子及结构
2.2将上述96孔板置于4℃温箱中孵育30min，然后加入5μL 1mM ATP，37℃下继续反应30min后取出室温冷却5min，加入50μLReagent，避光反应10min后，用酶标仪测量相对发光值RLU。
2.3采用如下公式计算药物酶活的抑制率：
药物酶活抑制率＝(待测药物化学发光值–阳性组化学发光平均值)/(阴性组化学发光平均值–阳性组化学发光平均值)×100％。
结果见图2，化合物K-252a对STK酶活的抑制率达66.3％以上。
3、IC50的测定
对上述实验中筛选出的抑制剂K-252a进行IC50测定。在黑色平底96孔板中，加入44μL酶活反应液，包含10mM MgCl2、10μM STK和pH 7.0的激酶缓冲液(50mM HEPES，1mM DTT和0.01％Brij35)，然后加入倍比稀释的化合物K-252a，每个浓度设置3个重复，并设置加STK阳性对照和不加STK阴性孔对照，将平板在4℃温箱中孵育30min，然后加入5μL 1mM ATP，37℃下继续反应30min后取出室温冷却5min，加入50μLReagent，避光反应10min后，用酶标仪测量相对发光值RLU。
酶活抑制率公式如下：
药物酶活抑制率＝(待测药物化学发光值–阳性组化学发光平均值)/(阴性组化学发光平均值–阳性组化学发光平均值)×100％。
结果见图3，化合物K-252A对STK酶活的IC50为13.81μM。
实施例2猪链球菌丝氨酸苏氨酸蛋白激酶STK抑制剂K-252a在猪链球菌生长中应用
挑取猪链球菌SC19菌株单菌落接种至含5％灭活牛血清的TSB培养基中过夜培养，然后将菌液转接至CDM培养基，调整OD600 nm为0.01，置于100孔生长曲线测定板中，并加入终浓度为50μM的抑制剂K-252a，同时设置猪链球菌SC19与stk基因缺失株Δstk(Hu Q,YaoL,Liao X,Zhang LS,Li HT,Li TT,Jiang QG,Tan MF,Li L,Draheim RR,Huang Q,ZhouR.Comparative Phenotypic,Proteomic,and Phosphoproteomic Analysis RevealsDifferent Roles of Serine/Threonine Phosphatase and Kinase in the Growth,CellDivision,and Pathogenicity of Streptococcus suis.Microorganisms.2021Nov 26；9(12):2442.doi:10.3390/microorganisms9122442.)分别为阳性对照和阴性对照，以加入相同体积的DMSO为空白对照，置于生长曲线测定仪中，在37℃条件下进行生长曲线测定。
结果见图4，K-252a能显著抑制猪链球菌SC19的生长。
Claims (1)
1.一种猪链球菌丝氨酸苏氨酸蛋白激酶的抑制剂在制备抗菌药物中的应用，其特征在于：所述的抗菌为抑制猪链球菌生长；所述的抑制剂为结构式如下所示的化合物：
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