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Inhibition of Clostridioides difficile Toxins TcdA and TcdB by Ambroxol

Clostridioides (C.) difficile produces the exotoxins TcdA and TcdB, which are the predominant virulence factors causing C. difficile associated disease (CDAD). TcdA and TcdB bind to target cells and are internalized via receptor-mediated endocytosis. Translocation of the toxins’ enzyme subunits from...

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Autores principales: Heber, Sebastian, Barthold, Lara, Baier, Jan, Papatheodorou, Panagiotis, Fois, Giorgio, Frick, Manfred, Barth, Holger, Fischer, Stephan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8764291/
https://www.ncbi.nlm.nih.gov/pubmed/35058787
http://dx.doi.org/10.3389/fphar.2021.809595
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author Heber, Sebastian
Barthold, Lara
Baier, Jan
Papatheodorou, Panagiotis
Fois, Giorgio
Frick, Manfred
Barth, Holger
Fischer, Stephan
author_facet Heber, Sebastian
Barthold, Lara
Baier, Jan
Papatheodorou, Panagiotis
Fois, Giorgio
Frick, Manfred
Barth, Holger
Fischer, Stephan
author_sort Heber, Sebastian
collection PubMed
description Clostridioides (C.) difficile produces the exotoxins TcdA and TcdB, which are the predominant virulence factors causing C. difficile associated disease (CDAD). TcdA and TcdB bind to target cells and are internalized via receptor-mediated endocytosis. Translocation of the toxins’ enzyme subunits from early endosomes into the cytosol depends on acidification of endosomal vesicles, which is a prerequisite for the formation of transmembrane channels. The enzyme subunits of the toxins translocate into the cytosol via these channels where they are released after auto-proteolytic cleavage. Once in the cytosol, both toxins target small GTPases of the Rho/Ras-family and inactivate them by mono-glucosylation. This in turn interferes with actin-dependent processes and ultimately leads to the breakdown of the intestinal epithelial barrier and inflammation. So far, therapeutic approaches to treat CDAD are insufficient, since conventional antibiotic therapy does not target the bacterial protein toxins, which are the causative agents for the clinical symptoms. Thus, directly targeting the exotoxins represents a promising approach for the treatment of CDAD. Lately, it was shown that ambroxol (Ax) prevents acidification of intracellular organelles. Therefore, we investigated the effect of Ax on the cytotoxic activities of TcdA and TcdB. Ax significantly reduced toxin-induced morphological changes as well as the glucosylation of Rac1 upon intoxication with TcdA and TcdB. Most surprisingly, Ax, independent of its effects on endosomal acidification, decreased the toxins’ intracellular enzyme activity, which is mediated by a catalytic glucosyltransferase domain. Considering its undoubted safety profile, Ax might be taken into account as therapeutic option in the context of CDAD.
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spelling pubmed-87642912022-01-19 Inhibition of Clostridioides difficile Toxins TcdA and TcdB by Ambroxol Heber, Sebastian Barthold, Lara Baier, Jan Papatheodorou, Panagiotis Fois, Giorgio Frick, Manfred Barth, Holger Fischer, Stephan Front Pharmacol Pharmacology Clostridioides (C.) difficile produces the exotoxins TcdA and TcdB, which are the predominant virulence factors causing C. difficile associated disease (CDAD). TcdA and TcdB bind to target cells and are internalized via receptor-mediated endocytosis. Translocation of the toxins’ enzyme subunits from early endosomes into the cytosol depends on acidification of endosomal vesicles, which is a prerequisite for the formation of transmembrane channels. The enzyme subunits of the toxins translocate into the cytosol via these channels where they are released after auto-proteolytic cleavage. Once in the cytosol, both toxins target small GTPases of the Rho/Ras-family and inactivate them by mono-glucosylation. This in turn interferes with actin-dependent processes and ultimately leads to the breakdown of the intestinal epithelial barrier and inflammation. So far, therapeutic approaches to treat CDAD are insufficient, since conventional antibiotic therapy does not target the bacterial protein toxins, which are the causative agents for the clinical symptoms. Thus, directly targeting the exotoxins represents a promising approach for the treatment of CDAD. Lately, it was shown that ambroxol (Ax) prevents acidification of intracellular organelles. Therefore, we investigated the effect of Ax on the cytotoxic activities of TcdA and TcdB. Ax significantly reduced toxin-induced morphological changes as well as the glucosylation of Rac1 upon intoxication with TcdA and TcdB. Most surprisingly, Ax, independent of its effects on endosomal acidification, decreased the toxins’ intracellular enzyme activity, which is mediated by a catalytic glucosyltransferase domain. Considering its undoubted safety profile, Ax might be taken into account as therapeutic option in the context of CDAD. Frontiers Media S.A. 2022-01-04 /pmc/articles/PMC8764291/ /pubmed/35058787 http://dx.doi.org/10.3389/fphar.2021.809595 Text en Copyright © 2022 Heber, Barthold, Baier, Papatheodorou, Fois, Frick, Barth and Fischer. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Heber, Sebastian
Barthold, Lara
Baier, Jan
Papatheodorou, Panagiotis
Fois, Giorgio
Frick, Manfred
Barth, Holger
Fischer, Stephan
Inhibition of Clostridioides difficile Toxins TcdA and TcdB by Ambroxol
title Inhibition of Clostridioides difficile Toxins TcdA and TcdB by Ambroxol
title_full Inhibition of Clostridioides difficile Toxins TcdA and TcdB by Ambroxol
title_fullStr Inhibition of Clostridioides difficile Toxins TcdA and TcdB by Ambroxol
title_full_unstemmed Inhibition of Clostridioides difficile Toxins TcdA and TcdB by Ambroxol
title_short Inhibition of Clostridioides difficile Toxins TcdA and TcdB by Ambroxol
title_sort inhibition of clostridioides difficile toxins tcda and tcdb by ambroxol
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8764291/
https://www.ncbi.nlm.nih.gov/pubmed/35058787
http://dx.doi.org/10.3389/fphar.2021.809595
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