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

Author

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

Subjects
Escherichia coli infections -- Care and treatment, Carbohydrates -- Research, Science and technology
Abstract

Infection with Shiga toxin (Stx)-producing Escherichia coil O157: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 ([K.sub.d] = 1.1 x [10.sup.-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 O157: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.

Published
2002

10. Oral Therapeutic Agents with Highly Clustered Globotriose for Treatment of Shiga ToxigenicEscherichia coliInfections

Author

Watanabe, Miho, primary, Matsuoka, Koji, additional, Kita, Eiji, additional, Igai, Katsura, additional, Higashi, Nobutaka, additional, Miyagawa, Atsushi, additional, Watanabe, Toshiyuki, additional, Yanoshita, Ryohei, additional, Samejima, Yuji, additional, Terunuma, Daiyo, additional, Natori, Yasuhiro, additional, and Nishikawa, Kiyotaka, additional

Published
2004
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17. Relapsing fever Borrelia binds to neolacto glycans and mediates rosetting of human erythrocytes.

Abstract

A hallmark of acute relapsing fever borreliosis is severe bacteremia. Some Borrelia species, such as B. duttonii and B. crocidurae, associate with erythrocytes and induce aggregation recognized as erythrocyte rosetting. Erythrocyte rosettes contribute to disease severity by increased tissue invasiveness (such as invasion of CNS and encephalitis), hemorrhaging, and reduced blood flow in affected microcapillaries. Here we report that relapsing fever Borrelia binds to neolacto (Galbeta4GlcNAcbeta3Galbeta4Glcbeta1)-carrying glycoconjugates that are present on human erythrocytes. This interaction is of low affinity but is compensated for by the multivalency of neo-lacto-oligosaccharides on the erythrocyte cell surface. Hence, the protein-carbohydrate interaction is dependent on multivalent neolacto-glycans to mediate binding.

Published
2009
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