Tailored cyclodextrin pore blocker protects mammalian cells from clostridium difficile binary toxin CDT.
Tailored cyclodextrin pore blocker protects mammalian cells from clostridium difficile binary toxin CDT.
复制标题
定制的环糊精孔隙阻滞剂可保护哺乳动物细胞免受艰难梭菌二元毒素CDT的侵害。
DOI：
10.3390/toxins6072097
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发表时间：
2014-07-15
期刊：
影响因子：
4.2
通讯作者：
Barth H
中科院分区：
文献类型：
--
作者：
Roeder M;Nestorovich EM;Karginov VA;Schwan C;Aktories K;Barth H
除了毒素A和B之外，一些艰难梭菌菌株还产生二元毒素艰难梭菌转移酶（CDT），其ADP-核糖基化肌动蛋白并且可能有助于这些菌株的高毒力。单独的结合和易位组分CDTb介导酶组分CDTa转运到哺乳动物靶细胞中。CDTb与细胞表面的受体结合，CDTa组装，CDTb/CDTa复合物被内化。在酸性内体中，CDTb介导CDTa递送到胞质溶胶中，最有可能是通过在内体膜中形成移位孔。我们证明了一种七倍对称带正电荷的β-环糊精衍生物，per-6-S-（3-氨甲基）苄硫基-β-环糊精，它是早期开发的炭疽杆菌，肉毒梭菌和产气荚膜梭菌的相关二元毒素的易位孔的有效抑制剂，保护细胞免受CDT中毒。孔阻滞剂不干扰CDTa催化的ADP-核糖基化肌动蛋白或毒素结合到Vero细胞，但抑制pH依赖性膜易位CDTa到胞质溶胶。总之，阳离子β-环糊精可以作为开发新的抗CDT产生菌的药理学策略的先导化合物。很难
Some Clostridium difficile strains produce, in addition to toxins A and B, the binary toxin Clostridium difficile transferase (CDT), which ADP-ribosylates actin and may contribute to the hypervirulence of these strains. The separate binding and translocation component CDTb mediates transport of the enzyme component CDTa into mammalian target cells. CDTb binds to its receptor on the cell surface, CDTa assembles and CDTb/CDTa complexes are internalised. In acidic endosomes, CDTb mediates the delivery of CDTa into the cytosol, most likely by forming a translocation pore in endosomal membranes. We demonstrate that a seven-fold symmetrical positively charged β-cyclodextrin derivative, per-6-S-(3-aminomethyl)benzylthio-β-cyclodextrin, which was developed earlier as a potent inhibitor of the translocation pores of related binary toxins of Bacillus anthracis, Clostridium botulinum and Clostridium perfringens, protects cells from intoxication with CDT. The pore blocker did not interfere with the CDTa-catalyzed ADP-ribosylation of actin or toxin binding to Vero cells but inhibited the pH-dependent membrane translocation of CDTa into the cytosol. In conclusion, the cationic β-cyclodextrin could serve as the lead compound in a development of novel pharmacological strategies against the CDT-producing strains of C. difficile.
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影响因子：
3.7
作者：
Beitzinger C;Bronnhuber A;Duscha K;Riedl Z;Huber-Lang M;Benz R;Hajós G;Barth H
通讯作者：
Barth H
影响因子：
2.9
作者：
Haug, G;Wilde, C;Barth, H
通讯作者：
Barth, H
影响因子：
64.8
作者：
JUST, I;SELZER, J;AKTORIES, K
通讯作者：
AKTORIES, K
影响因子：
2.9
作者：
Blöcker, D;Bachmeyer, C;Barth, H
通讯作者：
Barth, H
影响因子：
4.8
作者：
Blöcker, D;Pohlmann, K;Barth, H
通讯作者：
Barth, H