Functional amyloids in Streptococcus mutans, their use as targets of biofilm inhibition and initial characterization of SMU_63c
Functional amyloids in Streptococcus mutans, their use as targets of biofilm inhibition and initial characterization of SMU_63c
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DOI：
10.1099/mic.0.000443
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发表时间：
2017-04-01
期刊：
影响因子：
2.8
通讯作者：
Brady, L. Jeannine
中科院分区：
文献类型：
--
作者：
Besingi, Richard N.;Wenderska, Iwona B.;Brady, L. Jeannine
淀粉样蛋白已被鉴定为细菌生物膜细胞外基质的功能成分。变形链球菌是一种公认的龋病病原菌，也是一种生物膜居住者。除了已知的淀粉样粘附素P1(又称AGI/II，PAC)外，我们还发现变形链球菌壁相关蛋白A(WAPA)的天然抗原A衍生物和分泌蛋白SMU_63c也可以形成淀粉样纤维。结果表明，P1、WAPA和SMU_63c对生物膜的发育和结构有显著影响，免疫胶体金电子显微镜显示这三种蛋白均存在于生物膜的纤维细胞外基质中。我们还发现SMU_63c对生物膜细胞密度和遗传活性具有负调节作用。此外，自然产生的P1的C末端裂解产物C123(也称为AGII)被证明代表该蛋白的淀粉样蛋白部分。因此，P1和WAPA都代表被加工成导致淀粉样变的截断衍生物的索酸酶底物。我们目前的结果提示了一种新的机制，即某些细胞表面粘附素被处理，并有助于变形链球菌产生淀粉样蛋白的能力。我们进一步证明，多酚小分子单宁酸和表没食子儿茶素没食子酸酯和苯醌衍生物AA-861在体外都能抑制C123和抗原A的淀粉样纤化，也通过依赖于P1和WAPA的机制抑制变形链球菌生物膜的形成，表明这些蛋白是抗淀粉样蛋白化合物的治疗靶点。
Amyloids have been identified as functional components of the extracellular matrix of bacterial biofilms. Streptococcus mutans is an established aetiologic agent of dental caries and a biofilm dweller. In addition to the previously identified amyloidogenic adhesin P1 (also known as AgI/II, PAc), we show that the naturally occurring antigen A derivative of S. mutans wall-associated protein A (WapA) and the secreted protein SMU_63c can also form amyloid fibrils. P1, WapA and SMU_63c were found to significantly influence biofilm development and architecture, and all three proteins were shown by immunogold electron microscopy to reside within the fibrillar extracellular matrix of the biofilms. We also showed that SMU_63c functions as a negative regulator of biofilm cell density and genetic competence. In addition, the naturally occurring C-terminal cleavage product of P1, C123 (also known as AgII), was shown to represent the amyloidogenic moiety of this protein. Thus, P1 and WapA both represent sortase substrates that are processed to amyloidogenic truncation derivatives. Our current results suggest a novel mechanism by which certain cell surface adhesins are processed and contribute to the amyloidogenic capability of S. mutans. We further demonstrate that the polyphenolic small molecules tannic acid and epigallocatechin-3-gallate, and the benzoquinone derivative AA-861, which all inhibit amyloid fibrillization of C123 and antigen A in vitro, also inhibit S. mutans biofilm formation via P1- and WapA-dependent mechanisms, indicating that these proteins serve as therapeutic targets of anti-amyloid compounds.