Alternate identifier:
-
Related identifier:
(Is Supplement To) 10.1080/19490976.2023.2256695 - DOI
Creator/Author:
Papatheodorou, Panagiotis https://orcid.org/0000-0003-3571-695X [Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, Ulm University Medical Center]
Contributors:
(Researcher)
Schumacher, Judith [Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, Ulm University Medical Center]

(Researcher)
Nienhaus, Astrid [Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, Ulm University Medical Center]

(Researcher)
Heber, Sebastian [Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, Ulm University Medical Center]

(Researcher)
Chaves-Olarte, Esteban https://orcid.org/0000-0002-4840-2426 [Centro de Investigación en Enfermedades Tropicales and Facultad de Microbiología, Universidad de Costa Rica]

(Researcher)
Rodríguez, César https://orcid.org/0000-0001-5599-0652 [Centro de Investigación en Enfermedades Tropicales and Facultad de Microbiología, Universidad de Costa Rica]

(Project Leader)
Barth, Holger https://orcid.org/0000-0002-2706-3402 [Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, Ulm University Medical Center]
Title:
Schumacher et al (raw data)
Additional titles:
(Other) Exploring the inhibitory potential of the antiarrhythmic drug amiodarone against Clostridioides difficile toxins TcdA and TcdB
Description:
(Object) Zip file includes all figures of the Schumacher et al. manuscript with PDF files providing the original image data and Excel calculations that were used to generate the figures.
(Abstract) The intestinal pathogen Clostridioides difficile is the leading cause of antibiotic-associated diarrhea and pseudomembranous colitis in humans. The symptoms of C. difficile-associated diseases (CDADs) are directly associated with the pathogen’s toxins TcdA and TcdB, which enter host cells and inactivate Rho and/or Ras GTPases by glucosylation. Membrane cholesterol is crucial during the intoxication process of TcdA and TcdB, and likely involved during pore formation of both toxins in endosomal membranes, a key step after cellular uptake for the translocation of the glucosyltransferase domain of both toxins from endosomes into the host cell cytosol. The licensed drug amiodarone, a multichannel blocker commonly used in the treatment of cardiac dysrhythmias, is also capable of inhibiting endosomal acidification and, as shown recently, cholesterol biosynthesis. Thus, we were keen to investigate in vitro with cultured cells and human intestinal organoids, whether amiodarone preincubation protects from TcdA and/or TcdB intoxication. Amiodarone conferred protection against both toxins independently and in combination as well as against toxin variants from the clinically relevant, epidemic C. difficile strain NAP1/027. Further mechanistic studies suggested that amiodarone’s mode-of-inhibition involves also interference with the translocation pore of both toxins. Our study opens the possibility of repurposing the licensed drug amiodarone as a novel pan-variant antitoxin therapeutic in the context of CDADs.
Keywords:
Amiodarone
Clostridioides difficile infection
Toxin inhibitor
Drug repurposing
Drug repositioning
Membrane cholesterol
Related information:
(2157) PubChem ID of amiodarone
(C25H29I2NO3) Molecular formular of amiodarone
(645.3) Molecular weigth of amiodarone
Language:
English
Publishers:
Papatheodorou, Panagiotis
Production year:
Subject areas:
Medicine
Biochemistry
Biology
Chemistry
Life Science
Resource type:
(Collection) Raw data
Data source:
-
Software used:
-
Data processing:
-
Publication year:
Rights holders:
Papatheodorou, Panagiotis

Schumacher, Judith

Barth, Holger
Funding:
Deutsche Forschungsgemeinschaft - (BA 2087/8-1) Project number 450938962
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