EGA Protects Mammalian Cells from Clostridium difficile CDT, Clostridium perfringens Iota Toxin and Clostridium botulinum C2 Toxin
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...
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MDPI AG
2016-04-01
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| Series: | Toxins |
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| Online Access: | http://www.mdpi.com/2072-6651/8/4/101 |
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| author | Leonie Schnell Ann-Katrin Mittler Mirko Sadi Michel R. Popoff Carsten Schwan Klaus Aktories Andrea Mattarei Domenico Azarnia Tehran Cesare Montecucco Holger Barth |
| author_facet | Leonie Schnell Ann-Katrin Mittler Mirko Sadi Michel R. Popoff Carsten Schwan Klaus Aktories Andrea Mattarei Domenico Azarnia Tehran Cesare Montecucco Holger Barth |
| author_sort | Leonie Schnell |
| collection | DOAJ |
| description | 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. |
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| language | English |
| last_indexed | 2024-04-13T00:50:30Z |
| publishDate | 2016-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Toxins |
| spelling | doaj.art-f856a71baa684081927e2441a852324b2022-12-22T03:09:54ZengMDPI AGToxins2072-66512016-04-018410110.3390/toxins8040101toxins8040101EGA Protects Mammalian Cells from Clostridium difficile CDT, Clostridium perfringens Iota Toxin and Clostridium botulinum C2 ToxinLeonie Schnell0Ann-Katrin Mittler1Mirko Sadi2Michel R. Popoff3Carsten Schwan4Klaus Aktories5Andrea Mattarei6Domenico Azarnia Tehran7Cesare Montecucco8Holger Barth9Institute of Pharmacology and Toxicology, University of Ulm Medical Center, Albert-Einstein-Allee 11, 89081 Ulm, GermanyInstitute of Pharmacology and Toxicology, University of Ulm Medical Center, Albert-Einstein-Allee 11, 89081 Ulm, GermanyInstitute of Pharmacology and Toxicology, University of Ulm Medical Center, Albert-Einstein-Allee 11, 89081 Ulm, GermanyDepartment of Anaerobic Bacteria, Pasteur Institute, 75015 Paris, FranceInstitute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, 79104 Freiburg, GermanyInstitute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, 79104 Freiburg, GermanyDepartment of Chemical Sciences, University of Padova, 35121 Padova, ItalyDepartment of Biomedical Sciences, University of Padova, 35121 Padova, ItalyDepartment of Biomedical Sciences, University of Padova, 35121 Padova, ItalyInstitute of Pharmacology and Toxicology, University of Ulm Medical Center, Albert-Einstein-Allee 11, 89081 Ulm, GermanyThe 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.http://www.mdpi.com/2072-6651/8/4/101Clostridium difficile CDTClostridium perfringens iota toxinClostridium botulinum C2 toxinbinary toxinEGA |
| spellingShingle | Leonie Schnell Ann-Katrin Mittler Mirko Sadi Michel R. Popoff Carsten Schwan Klaus Aktories Andrea Mattarei Domenico Azarnia Tehran Cesare Montecucco Holger Barth EGA Protects Mammalian Cells from Clostridium difficile CDT, Clostridium perfringens Iota Toxin and Clostridium botulinum C2 Toxin Toxins Clostridium difficile CDT Clostridium perfringens iota toxin Clostridium botulinum C2 toxin binary toxin EGA |
| title | EGA Protects Mammalian Cells from Clostridium difficile CDT, Clostridium perfringens Iota Toxin and Clostridium botulinum C2 Toxin |
| title_full | EGA Protects Mammalian Cells from Clostridium difficile CDT, Clostridium perfringens Iota Toxin and Clostridium botulinum C2 Toxin |
| title_fullStr | EGA Protects Mammalian Cells from Clostridium difficile CDT, Clostridium perfringens Iota Toxin and Clostridium botulinum C2 Toxin |
| title_full_unstemmed | EGA Protects Mammalian Cells from Clostridium difficile CDT, Clostridium perfringens Iota Toxin and Clostridium botulinum C2 Toxin |
| title_short | EGA Protects Mammalian Cells from Clostridium difficile CDT, Clostridium perfringens Iota Toxin and Clostridium botulinum C2 Toxin |
| title_sort | ega protects mammalian cells from clostridium difficile cdt clostridium perfringens iota toxin and clostridium botulinum c2 toxin |
| topic | Clostridium difficile CDT Clostridium perfringens iota toxin Clostridium botulinum C2 toxin binary toxin EGA |
| url | http://www.mdpi.com/2072-6651/8/4/101 |
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