Inhibitions of the translocation pore of Clostridium botulinum C2 toxin by tailored azolopyridinium salts protects human cells from intoxication

Anika Bronnhuber, Elke Maier, Zsuzsanna Riedl, György Hajós, Roland Benz, Holger Barth

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

C2 toxin from Clostridium botulinum represents the prototype of clostridial binary actin ADP-ribosylating toxins which destroy the actin-cytoskeleton of mammalian cells and cause severe enteric diseases in humans and animals. After receptor-mediated endocytosis of the C2 toxin complex, the binding/translocation component C2IIa forms a heptameric transmembrane pore in membranes of acidified endosomal vesicles. The separate ADP-ribosyltransferase component C2I translocates through this C2IIa-pore from the endosomal lumen into the cytosol.Here we demonstrate that positively charged heterocyclic azolopyridinium salts which were developed as pore blockers for the anthrax toxins, efficiently protect cultured mammalian cells from intoxication with C2 toxin. The inhibitors had no effects on enzyme activity of C2I or receptor binding of C2 toxin but inhibited the pH-dependent membrane translocation of C2I in living cells, most likely by blocking the C2IIa-translocation pores. In vitro, the substances blocked C2IIa-pores in black lipid bilayer membranes when applied to the cis-side of the membrane which corresponds to the endosomal lumen of cells. Thus, heterocyclic azolopyridinium salts could represent lead compounds for development of novel therapeutics against binary clostridial toxins.

Original languageEnglish
Pages (from-to)25-33
Number of pages9
JournalToxicology
Volume316
Issue number1
DOIs
Publication statusPublished - Feb 28 2014

Keywords

  • Anthrax toxin
  • Azolopyridinium salts
  • Clostridium botulinum C2 toxin
  • Membrane transport
  • Pore blockers

ASJC Scopus subject areas

  • Toxicology

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