Semicarbazone EGA Inhibits Uptake of Diphtheria Toxin into Human Cells and Protects Cells from Intoxication
Leonie Schnell 1, Ann-Katrin Mittler 1, Andrea Mattarei 2, Domenico Azarnia Tehran 3
, Cesare Montecucco 3 and Holger Barth 1,*
, Cesare Montecucco 3 and Holger Barth 1,*
1
Institute of Pharmacology and Toxicology, University of Ulm Medical Center, Albert-Einstein-Allee 11, 89081 Ulm, Germany
2
Department of Chemical Sciences, University of Padova, 35121 Padova, Italy
3
Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy
*
Author to whom correspondence should be addressed.
Academic Editor: Jun Sakurai
Toxins 2016, 8(7), 221; https://doi.org/10.3390/toxins8070221
Received: 6 May 2016 / Revised: 25 June 2016 / Accepted: 7 July 2016 / Published: 15 July 2016
(This article belongs to the Special Issue Novel Pharmacological Inhibitors for Bacterial Protein Toxins)
Abstract
Diphtheria toxin is a single-chain protein toxin that invades human cells by receptor-mediated endocytosis. In acidic endosomes, its translocation domain inserts into endosomal membranes and facilitates the transport of the catalytic domain (DTA) from endosomal lumen into the host cell cytosol. Here, DTA ADP-ribosylates elongation factor 2 inhibits protein synthesis and leads to cell death. The compound 4-bromobenzaldehyde N-(2,6-dimethylphenyl)semicarbazone (EGA) has been previously shown to protect cells from various bacterial protein toxins which deliver their enzymatic subunits from acidic endosomes to the cytosol, including Bacillus anthracis lethal toxin and the binary clostridial actin ADP-ribosylating toxins C2, iota and Clostridium difficile binary toxin (CDT). Here, we demonstrate that EGA also protects human cells from diphtheria toxin by inhibiting the pH-dependent translocation of DTA across cell membranes. The results suggest that EGA might serve for treatment and/or prevention of the severe disease diphtheria. View Full-TextKeywords:
diphtheria; diphtheria toxin; cellular uptake; membrane transport; EGA
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Schnell, L.; Mittler, A.-K.; Mattarei, A.; Tehran, D.A.; Montecucco, C.; Barth, H. Semicarbazone EGA Inhibits Uptake of Diphtheria Toxin into Human Cells and Protects Cells from Intoxication. Toxins 2016, 8, 221.
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