2026-06-25T05:36:38Zhttps://www.radar-service.eu/oai/OAIHandler

10.22000/9422023-11-15T14:36:23Zradar4chem

10.22000/942 Papatheodorou, Panagiotis Panagiotis Papatheodorou 0000-0003-3571-695X Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, Ulm University Medical Center Papatheodorou, Panagiotis 2023 2023 Medicine Biochemistry Biology Chemistry Life Science Amiodarone Clostridioides difficile infection Toxin inhibitor Drug repurposing Drug repositioning Membrane cholesterol Raw data Open Access Creative Commons Attribution 4.0 International Papatheodorou, Panagiotis Schumacher, Judith Barth, Holger Schumacher, Judith Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, Ulm University Medical Center Nienhaus, Astrid Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, Ulm University Medical Center Heber, Sebastian Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, Ulm University Medical Center Chaves-Olarte, Esteban 0000-0002-4840-2426 Centro de Investigación en Enfermedades Tropicales and Facultad de Microbiología, Universidad de Costa Rica Rodríguez, César 0000-0001-5599-0652 Centro de Investigación en Enfermedades Tropicales and Facultad de Microbiología, Universidad de Costa Rica Barth, Holger 0000-0002-2706-3402 Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, Ulm University Medical Center 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. 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. PubChem ID of amiodarone Molecular formular of amiodarone Molecular weigth of amiodarone en 10.1080/19490976.2023.2256695 Deutsche Forschungsgemeinschaft 501100001659 Project number 450938962 BA 2087/8-1 application/x-tar