CN113150073B - 革兰氏阴性菌八型分泌系统抑制剂及其应用 - Google Patents
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Abstract
本发明提供革兰氏阴性菌八型分泌系统抑制剂及其应用。所述抑制剂是指靶向结合革兰氏阴性菌八型分泌系统的分泌通道蛋白CsgG，且能够限制或封闭细菌八型分泌系统的分泌通道并可与CsgF竞争结合CsgG的物质。本发明示例性地展示了大肠杆菌八型分泌系统的多肽抑制剂，其氨基酸序列如SEQ ID NO:1所示。通过改变分泌孔道环境以及通过与天然蛋白组分(CsgF)竞争性结合分泌通道蛋白(CsgG)来抑制细菌八型分泌系统，进而抑制Curli生成。本发明有望推广应用于其他类似通道蛋白的抑制中。
Description
技术领域
本发明涉及结构生物学，具体地说，涉及革兰氏阴性菌八型分泌系统抑制剂及其应用。
背景技术
二十世纪初，抗生素的出现为很多细菌感染疾病提供了有效的治疗。然而，由于抗生素滥用等情况的存在，导致目前细菌的抗性问题十分严重。因此，发现新的药物靶标以及新的抑制机制是目前抗菌药物研发领域关注的焦点。
细菌生物被膜是指细菌以及细菌外部包裹细菌的一系列多聚体，它在保护细菌免受抗生素侵袭，外界环境压力，宿主免疫系统攻击等方面发挥重要作用。同时，多种疾病被认为和生物被膜密切相关，包括囊胞性纤维症，慢性中耳炎和尿路感染等。
大肠杆菌以及一些其他的肠杆菌科细菌通过分泌底物CsgA在细菌表面聚集生成功能淀粉样蛋白纤维Curli，该成分作为细菌生物被膜的重要组成部分对保护细菌起着重要作用。同时，Curli可以通过调节细胞-细胞以及细胞-表面的粘附作用从而促使细菌粘附到哺乳细胞，植物细胞以及一些固体比如医疗器械等表面从而促进细菌的传播。基于以上研究，通过抑制Curli生成，在抗生素等药物帮助下可以实现对致病菌的有效防治。由于Curli发挥的重要作用，使其成为相关药物研发的重要靶标。早期针对该靶标的抑制剂研究主要是集中在如何抑制底物在体外聚集形成淀粉样蛋白纤维，代表性小分子抑制剂包括吡啶酮类小分子FN075和BibC6(Cegelski,L.et al.,Small-molecule inhibitors targetEscherichia coli amyloid biogenesis and biofilm formation.Nat Chem Biol.5 12(2009))等。然而，这些小分子抑制剂是如何抑制底物在体外聚集形成淀粉样蛋白纤维的机制并不明朗，主要通过盲筛获得小分子抑制剂，费时费力。因此，亟待开发新的能够有效抑制Curli生成的物质。
发明内容
本发明的目的是提供革兰氏阴性菌八型分泌系统抑制剂及其应用。
本发明构思如下：通过以Curli分泌系统位于细菌外膜的分泌通道蛋白CsgG为靶标，设计了一个多肽抑制剂PeptideNN17R，该抑制剂通过物理性封闭分泌通道CsgG，抑制底物CsgA的分泌从而达到抑制Curli生成的目的。
为了实现本发明目的，第一方面，本发明提供革兰氏阴性菌八型分泌系统抑制剂，所述抑制剂是指靶向结合革兰氏阴性菌八型分泌系统的分泌通道蛋白CsgG，且能够限制细菌八型分泌系统的分泌通道并可与CsgF竞争结合CsgG的物质。
本发明中，CsgF是指科林(Curli)结合蛋白，或科林(Curli)装配因子。
本发明中，所述革兰氏阴性菌是指包含Curli分泌系统的革兰氏阴性菌，优选埃希氏菌属(Escherichia)细菌，更优选大肠杆菌(Escherichia coli)。例如，肠毒性大肠杆菌。
所述抑制剂可以是大分子、小分子化合物或多肽。
优选地，大肠杆菌八型分泌系统抑制剂为多肽(PeptideNN17R)，所述多肽包含如下的氨基酸序列或由其组成：
i)、如SEQ ID NO:1所示的氨基酸序列；或
ii)、在i)的N端和/或C端连接标签得到的氨基酸序列；或
iii)、i)或ii)的氨基酸序列经取代、缺失和/或增加一个或多个氨基酸得到的具有相同功能的多肽。
第二方面，本发明提供含有所述抑制剂的抗菌药物或组合物。
第三方面，本发明提供含有所述抑制剂的杀菌剂或防腐剂。
第四方面，本发明提供所述抗菌剂的以下任一应用：
1)用于制备抗菌药物或组合物；
2)用于制备杀菌剂或防腐剂；
3)用于抗菌、防腐、消毒。
所述抗菌药物或组合物、杀菌剂或防腐剂中至少还包含一种抗菌活性成分。
借由上述技术方案，本发明至少具有下列优点及有益效果：
本发明提供一类靶向革兰氏阴性菌八型分泌系统分泌通道蛋白(CsgG)的抑制剂，其是根据天然蛋白(CsgF)结构而设计的多肽抑制剂。本发明首次发现，通过限制分泌孔道以及通过与天然蛋白组分(CsgF)竞争性结合分泌通道蛋白(CsgG)来抑制细菌八型分泌系统，进而抑制Curli生成。本发明有望推广应用于其他类似通道蛋白的抑制中。
本发明所针对的靶标蛋白(CsgG)位于细菌外膜，因此该抑制剂无需跨膜即可以发挥功能，避免了药物分子难以跨膜的问题。同时，该抑制剂是通过直接抑制底物CsgA的分泌发挥作用，抑制机制清晰明确，为后续针对该靶标的抑制剂研发和设计提供参考。
附图说明
图1为本发明实施例1中使用多肽抑制剂PeptideNN17R进行刚果红表型实验。结果表明该抑制剂在一定浓度时，有十分明显的细胞表型抑制。
图2为本发明实施例1中以截短体GTMTFQFRNPNFGGR作为抑制剂的细胞表型实验结果。
具体实施方式
以下实施例用于说明本发明，但不用来限制本发明的范围。若未特别指明，实施例均按照常规实验条件，如Sambrook等分子克隆实验手册(Sambrook J&Russell DW,Molecular Cloning:a Laboratory Manual,2001)，或按照制造厂商说明书建议的条件。实施例1大肠杆菌八型分泌系统抑制剂的获得
大肠杆菌八型分泌系统可参见Nenninger,A.A.et al.,Localized andefficient curli nucleation requires the chaperone-like amyloid assemblyprotein CsgF.Proc Natl Acad Sci U S A.106 3(2009),Robinson,L.S.et al.,Secretion of curli fibre subunits is mediated by the outer membrane-localizedCsgG protein.Mol Microbiol.59 3(2006)。CsgG和CsgF一起组装组成了一个九聚体的环形分泌通道，镶嵌在革兰氏阴性菌的外膜上。CsgF位于细菌的外表面，与由CsgA和CsgB两种底物蛋白形成的科林(Curli)纤维连接，使得科林纤维可以黏附于细菌表面。
发明人发现，CsgF缺失的大肠杆菌BW25113菌株通过回补突变体CsgF N17R(CsgF蛋白的第17个氨基酸由Asn变为Arg)可以导致刚果红表型缺失(刚果红表型缺失意味着没有Curli的生成)，因此考虑以CsgF N17R的衍生物作为抑制剂。由于CsgF的C末端不参与和Csg的相互作用，故选择CsgF的N末端。N末端有36个氨基酸(氨基酸序列为GTMTFQFRNPNFGGNPRNGAFLLNSAQAQNSYKDPS)，考虑到氨基酸人工合成的成本以及作为多肽抑制剂的大小，以CsgF蛋白的第17个氨基酸为分界点，分别设计并合成了PeptideNN17R(氨基酸序列为GTMTFQFRNPNFGGNPR，SEQ ID NO:1)和PeptideCN17R(氨基酸序列为RNGAFLLNSAQAQNSYKDPS)。经过大肠杆菌BW25113刚果红表型的验证，结果发现PeptideNN17R具有很好的抑制表型，进一步通过电镜结构解析发现该抑制剂的靶标确实是八型分泌系统(T8SS)位于外膜的分泌通道蛋白CsgG。
在多肽抑制剂PeptideNN17R的刚果红表型实验中，通过设置如图1所示的抑制剂浓度梯度，发现抑制剂浓度大于1μM时抑制效果明显(颜色越红表明Curli分泌越多，颜色偏白表示Curli分泌被抑制)。
具体实验方法如下：
将野生型BW25113菌株过夜培养，取5μL过夜培养的菌液(OD600＝3)滴在刚果红培养基上，自然风干。
将上述刚果红培养基放在26℃的恒温培养箱中培养48h，观察细菌颜色并拍照。
刚果红培养基配制：称取1g酵母提取物，10g酪蛋白水解物，20g琼脂糖以及90mg刚果红粉末，加水至1L，121℃高压灭菌30min，等温度降至60-70℃后，加入抗生素倒平板。
发明人还同时设计了GTMTFQFRNPNFGGR截短体并进行刚果红实验，实验步骤同上。刚果红表型结果显示，截短体(GTMTFQFRNPNFGGR)在浓度为10μM时，抑制表型仍然不明显(图2)。
虽然，上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述，但在本发明基础上，可以对之做一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。
参考文献:
[1]Goyal,P.et al.,Structural and mechanistic insights into thebacterial amyloid secretion channel CsgG.NATURE 516 250(2014).
[2]Schubeis,T.et al.,Structural and functional characterization ofthe Curli adaptor protein CsgF.FEBS LETT 592 1020(2018).
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<110> 清华大学
<120> 革兰氏阴性菌八型分泌系统抑制剂及其应用
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Claims (5)
1.革兰氏阴性菌八型分泌系统抑制剂，其特征在于，所述抑制剂为如SEQ ID NO:1所示的多肽。
2.含有权利要求1所述抑制剂的抗菌药物或组合物。
3.含有权利要求1所述抑制剂的杀菌剂或防腐剂。
4.权利要求1所述抑制剂的以下任一应用：
1）用于制备抗菌药物或组合物；
2）用于制备杀菌剂或防腐剂；
3）用于防腐。
5.根据权利要求4所述的应用，其特征在于，所述抗菌药物或组合物、杀菌剂或防腐剂中至少还包含一种抗菌活性成分。
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| Assembly and substrate recognition of curli biogenesis system;Zhaofeng Yan等;《NATURE COMMUNICATIONS》;20200113;第11卷;文章号241 * |
| Small-molecule inhibitors target Escherichia coli amyloid biogenesis and biofilm formation;Lynette Cegelski等;《NATURE CHEMICAL BIOLOGY》;20091025;第5卷(第12期);第913-919页 * |
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