A therapeutic agent with oriented carbohydrates for treatment of infections by Shiga toxin-producing Escherichia coli O157:H7

Kiyotaka Nishikawa, Koji Matsuoka, Eiji Kita, Noriko Okabe, Masashi Mizuguchi, Kumiko Hino, Shinobu Miyazawa, Chisato Yamasaki, Junken Aoki, Sachio Takashima, Yoshio Yamakawa, Masahiro Nishijima, Daiyo Terunuma, Hiroyoshi Kuzuhara, Yasuhiro Natori

Research output: Contribution to journalArticlepeer-review

163 Citations (Scopus)

Abstract

Infection with Shiga toxin (Stx)-producing Escherichia coli 0157:H7, which causes diarrhea and hemorrhagic colitis in humans, often results in fatal systemic complications, such as neurological damage and hemolytic-uremic syndrome. Because Stx circulating in the blood is a major causative factor of these complications, the development of a Stx neutralizer that functions in the circulation holds promise as a viable therapy. Here we developed a series of carbosilane dendrimers, in which trisaccharides of globotriaosyl ceramide, a receptor for Stx, were variously oriented at their termini (referred to as SUPER TWIG), and identified a SUPER TWIG with six trisaccharides as a Stx neutralizer functioning in the circulation. This SUPER TWIG specifically bound to Stx with high affinity (Kd = 1.1 x 10-6 M) and inhibited the incorporation of the toxin into target cells. Intravenous administration of the SUPER TWIG along with Stx to mice substantially reduced the fatal brain damage and completely suppressed the lethal effect of Stx. Moreover, the SUPER TWIG protected mice from challenge with a fatal dose of E. coli 0157:H7, even when administered after the establishment of the infection, The SUPER TWIG neutralized Stx in vivo by a mechanism in which the accumulation and immediate degradation of Stx by phagocytic macrophages present in the reticuloendothelial system were induced. Taken together, our findings indicate that this SUPER TWIG is therapeutic agent against infections by Stx-producing E. coli.

Original languageEnglish
Pages (from-to)7669-7674
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number11
DOIs
Publication statusPublished - 2002 May 28

ASJC Scopus subject areas

  • General

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