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Neutralizing Activity of Polyvalent Gb 3 , Gb 2 and Galacto‐Trehalose Models against Shiga Toxins
Author(s) -
Neri Paola,
Nagano Saori Itoh,
Yokoyama Shinichiro,
Dohi Hirofumi,
Kobayashi Kazukiyo,
Miura Tsuyoshi,
Inazu Toshiyuki,
Sugiyama Tsuyoshi,
Nishida Yoshihiro,
Mori Hiroshi
Publication year - 2007
Publication title -
microbiology and immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.664
H-Index - 70
eISSN - 1348-0421
pISSN - 0385-5600
DOI - 10.1111/j.1348-0421.2007.tb03944.x
Subject(s) - shiga toxin , in vivo , trehalose , microbiology and biotechnology , biology , cytotoxicity , escherichia coli , toxin , shiga like toxin , in vitro , biochemistry , gene
Shiga toxin (Stx) is one of the most critical factors in the development of hemolytic uremic syndrome and other systemic complications following enterohemorrhagic Escherichia coli (EHEC) infection. Substances neutralizing Stx by interfering with toxin‐receptor binding have been explored as therapeutic candidates for EHEC infection. In this study, we examined globotriaosyl (Gb 3 ), galabiosyl (Gb 2 ) and galacto‐trehalose, each of which was synthetically conjugated with a polyacrylamide backbone, for Stx‐neutralizing activity. Galacto‐trehalose was designed as a Gb 2 mimicking, unnatural Stx‐ligand that was expected to show tolerance to enzymatic degradation in vivo . Galacto‐trehalose copolymer showed neutralizing activity against Stx‐1 but not Stx‐2 in a HeLa cell cytotoxicity assay. It was thought that galacto‐trehalose copolymer could be a lead compound for the treatment of Stx‐mediated diseases, although it requires modification to show neutralizing activity to Stx‐2. The Gb 3 copolymer with high sugar unit density showed stronger neutralizing activity against Stx‐2 than those with lower density. However, the density‐dependency of the neutralizing activity was less obvious against Stx‐1. Intravenous administration of the Gb3 copolymer prevented death in mice lethally infected with Stx‐1‐ and Stx‐2‐producing E. coli O157:H7. Thus, we demonstrated that the artificial Gb 3 copolymer could neutralize Stx‐1 and the more clinically relevant Stx‐2 in vitro and effectively inhibit Stx toxicity in vivo .