Oral therapeutic agents with highly clustered globotriose for treatment of Shiga toxigenic Escherichia coli infections.

Abstract

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.

• Authors: Miho Watanabe, Koji Matsuoka, Eiji Kita, Katsura Igai, Nobutaka Higashi, Atsushi Miyagawa, Toshiyuki Watanabe, Ryohei Yanoshita, Yuji Samejima, Daiyo Terunuma, Yasuhiro Natori, Kiyotaka Nishikawa
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 189 Issue 3 Pg. 360-8 (Feb 01 2004) ISSN: 0022-1899 [Print] United States
• PMID: 14745692 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Polymers
• Receptors, Cell Surface
• Shiga Toxin 1
• Shiga Toxin 2
• Shiga Toxins
• Trihexosylceramides
• Trisaccharides
• Acrylamide
• globotriose
• globotriaosylceramide

Topics

• Acrylamide (chemistry, therapeutic use)
• Animals
• Brain Chemistry
• Carbohydrate Sequence
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Escherichia coli Infections (drug therapy, prevention & control)
• Escherichia coli O157 (metabolism, pathogenicity)
• Female
• Hemolytic-Uremic Syndrome (prevention & control)
• Mice
• Mice, Inbred C57BL
• Molecular Sequence Data
• Polymers (chemistry, therapeutic use)
• Protein Binding
• Receptors, Cell Surface (metabolism)
• Shiga Toxin 1 (metabolism)
• Shiga Toxin 2 (metabolism)
• Shiga Toxins (analysis, antagonists & inhibitors, metabolism)
• Trihexosylceramides (metabolism, therapeutic use)
• Trisaccharides (chemistry, therapeutic use)