A therapeutic agent with oriented carbohydrates for treatment of infections by Shiga toxin-producing Escherichia coli O157:H7.
Infection with Shiga toxin (Stx)-producing Escherichia coli 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(d) = 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 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.
Nishikawa
Kiyotaka
K
Department of Clinical Pharmacology, Research Institute, International Medical Center of Japan, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan. knishika@ri.imcj.go.jp
Matsuoka
Koji
K
Kita
Eiji
E
Okabe
Noriko
N
Mizuguchi
Masashi
M
Hino
Kumiko
K
Miyazawa
Shinobu
S
Yamasaki
Chisato
C
Aoki
Junken
J
Takashima
Sachio
S
Yamakawa
Yoshio
Y
Nishijima
Masahiro
M
Terunuma
Daiyo
D
Kuzuhara
Hiroyoshi
H
Natori
Yasuhiro
Y
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002241:Carbohydrates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D015195:Drug Design; D004927:Escherichia coli Infections / Q000188:drug therapy*; D019453:Escherichia coli O157; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D022621:Shiga Toxin / Q000096:biosynthesis* / Q000235:genetics; D012821:Silanes / Q000138:chemical synthesis* / Q000627:therapeutic use; D014162:Transfection; D014312:Trisaccharides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D014709:Vero Cells
D000900:Anti-Bacterial Agents; D002241:Carbohydrates; D011993:Recombinant Fusion Proteins; D012821:Silanes; D014312:Trisaccharides; D022621:Shiga Toxin; D005982:Glutathione Transferase