ABSTRACT
Infection with Shiga toxin (Stx)-producing Escherichia coli (STEC), including O157:H7, causes bloody diarrhea and hemorrhagic colitis in humans, occasionally resulting in fatal systemic complications, such as neurological damage and hemolytic-uremic syndrome. Because Stx is a major virulence factor of the infectious disease, a series of Shiga toxin neutralizers with various structural characteristics has been developed as promising therapeutic agents. Most of these agents function to bind to the toxin directly and inhibit the binding to its receptor present on the target cells. Other neutralizers do not inhibit receptor binding but induce aberrant intracellular transport of the toxin, resulting in effective detoxification. Such a novel type of Stx neutralizer provides a new therapeutic strategy against STEC infections. Here, recent progress of the development of Stx neutralizers is reviewed.
Subject(s)
Anti-Bacterial Agents/chemistry , Escherichia coli Infections/drug therapy , Peptides/administration & dosage , Shiga Toxin 1/antagonists & inhibitors , Shiga Toxin 2/antagonists & inhibitors , Trihexosylceramides/administration & dosage , Animals , Anti-Bacterial Agents/therapeutic use , Binding Sites/drug effects , Combinatorial Chemistry Techniques/methods , Drug Design , Endoplasmic Reticulum/metabolism , Escherichia coli O157/metabolism , Globosides/metabolism , Hemolytic-Uremic Syndrome/microbiology , Humans , Macrophages, Peritoneal/metabolism , Mice , Peptides/chemical synthesis , Polymers/pharmacology , Polymers/therapeutic use , Rabbits , Serum Amyloid P-Component/metabolism , Serum Amyloid P-Component/therapeutic use , Shiga Toxin 1/chemistry , Shiga Toxin 2/chemistry , Silanes/chemical synthesis , Silanes/therapeutic use , Trisaccharides/chemical synthesis , Trisaccharides/therapeutic use , Virulence Factors/metabolismABSTRACT
Fabry disease is an X-linked recessive disorder in which affected persons lack alpha-galactosidase A (alpha -GalA), which leads to excess glycosphingolipids in tissues, mainly globotriaosylceramide (Gb3). Gb3 is the cellular receptor for Shiga toxin (Stx), the primary virulence factor of enterohemorrhagic Escherichia coli. alpha-GalA-knockout mice were significantly protected against lethal intraperitoneal doses of Stx2 or oral doses of Stx2-expressing bacteria, compared with wild-type (wt) control mice. Kidneys of moribund wt mice revealed tubular necrosis, but no histopathologic changes were observed in Gb3-overexpressing mice. Reducing Gb3 levels in alpha-GalA-knockout mice by the intravenous injection of recombinant human alpha-GalA restored the susceptibility of knockout mice to lethal doses of Stx2. These results suggest that excess amounts of Gb3 in alpha-GalA-deficient mice may impair toxin delivery to susceptible tissues.
