Watanabe Miho, Matsuoka Koji, Kita Eiji, Igai Katsura, Higashi Nobutaka, Miyagawa Atsushi, Watanabe Toshiyuki, Yanoshita Ryohei, Samejima Yuji, Terunuma Daiyo, Natori Yasuhiro, Nishikawa Kiyotaka
Department of Clinical Pharmacology, Research Institute, International Medical Center of Japan, Tokyo, Japan.
J Infect Dis. 2004 Feb 1;189(3):360-8. doi: 10.1086/381124. Epub 2004 Jan 21.
Shiga toxin (Stx) is a major virulence factor in infection with Stx-producing Escherichia coli (STEC). We developed a series of linear polymers of acrylamide, each with a different density of trisaccharide of globotriaosylceramide (Gb3), which is a receptor for Stx, and identified Gb3 polymers with highly clustered trisaccharides as Stx adsorbents functioning in the gut. The Gb3 polymers specifically bound to both Stx1 and Stx2 with high affinity and markedly inhibited the cytotoxic activities of these toxins. Oral administration of the Gb3 polymers protected mice after administration of a fatal dose of E. coli O157:H7, even when the polymers were administered after the infection had been established. In these mice, the serum level of Stx was markedly reduced and fatal brain damage was substantially suppressed, which suggests that the Gb3 polymers entrap Stx in the gut and prevent its entrance into the circulation. These results indicate that the Gb3 polymers can be used as oral therapeutic agents that function in the gut against STEC infections.
志贺毒素（Stx）是产志贺毒素大肠杆菌（STEC）感染中的主要毒力因子。我们开发了一系列丙烯酰胺线性聚合物，每种聚合物的 globotriaosylceramide（Gb3）三糖密度不同，Gb3 是 Stx 的受体，我们鉴定出具有高度聚集三糖的 Gb3 聚合物作为在肠道中起作用的 Stx 吸附剂。Gb3 聚合物以高亲和力特异性结合 Stx1 和 Stx2，并显著抑制这些毒素的细胞毒性活性。口服 Gb3 聚合物可在给予致命剂量的大肠杆菌 O157:H7 后保护小鼠，即使在感染已确立后给予聚合物也是如此。在这些小鼠中，Stx 的血清水平显著降低，致命的脑损伤得到了显著抑制，这表明 Gb3 聚合物在肠道中捕获 Stx 并阻止其进入循环。这些结果表明，Gb3 聚合物可作为在肠道中发挥作用以对抗 STEC 感染的口服治疗剂。
