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Toxins 2016, 8(4), 101; doi:10.3390/toxins8040101

EGA Protects Mammalian Cells from Clostridium difficile CDT, Clostridium perfringens Iota Toxin and Clostridium botulinum C2 Toxin

1
Institute of Pharmacology and Toxicology, University of Ulm Medical Center, Albert-Einstein-Allee 11, 89081 Ulm, Germany
2
Department of Anaerobic Bacteria, Pasteur Institute, 75015 Paris, France
3
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, 79104 Freiburg, Germany
4
Department of Chemical Sciences, University of Padova, 35121 Padova, Italy
5
Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy
Contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Shin-ichi Miyoshi
Received: 25 January 2016 / Revised: 22 March 2016 / Accepted: 24 March 2016 / Published: 1 April 2016
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Abstract

The pathogenic bacteria Clostridium difficile, Clostridium perfringens and Clostridium botulinum produce the binary actin ADP-ribosylating toxins CDT, iota and C2, respectively. These toxins are composed of a transport component (B) and a separate enzyme component (A). When both components assemble on the surface of mammalian target cells, the B components mediate the entry of the A components via endosomes into the cytosol. Here, the A components ADP-ribosylate G-actin, resulting in depolymerization of F-actin, cell-rounding and eventually death. In the present study, we demonstrate that 4-bromobenzaldehyde N-(2,6-dimethylphenyl)semicarbazone (EGA), a compound that protects cells from multiple toxins and viruses, also protects different mammalian epithelial cells from all three binary actin ADP-ribosylating toxins. In contrast, EGA did not inhibit the intoxication of cells with Clostridium difficile toxins A and B, indicating a possible different entry route for this toxin. EGA does not affect either the binding of the C2 toxin to the cells surface or the enzyme activity of the A components of CDT, iota and C2, suggesting that this compound interferes with cellular uptake of the toxins. Moreover, for C2 toxin, we demonstrated that EGA inhibits the pH-dependent transport of the A component across cell membranes. EGA is not cytotoxic, and therefore, we propose it as a lead compound for the development of novel pharmacological inhibitors against clostridial binary actin ADP-ribosylating toxins. View Full-Text
Keywords: Clostridium difficile CDT; Clostridium perfringens iota toxin; Clostridium botulinum C2 toxin; binary toxin; EGA Clostridium difficile CDT; Clostridium perfringens iota toxin; Clostridium botulinum C2 toxin; binary toxin; EGA
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Schnell, L.; Mittler, A.-K.; Sadi, M.; Popoff, M.R.; Schwan, C.; Aktories, K.; Mattarei, A.; Tehran, D.A.; Montecucco, C.; Barth, H. EGA Protects Mammalian Cells from Clostridium difficile CDT, Clostridium perfringens Iota Toxin and Clostridium botulinum C2 Toxin. Toxins 2016, 8, 101.

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