An intestinal bacterium known as a hospital bug can be kept in check by a heart drug. This surprising conclusion was reached by a group of researchers led by pharmacologists and toxicologists Panagiotis Papatheodorou and Holger Barth. As they were able to show, the drug amiodarone inhibits certain cytotoxins of the intestinal pathogen C. difficile. The results of this international collaboration project have now been published in the scientific journal Gut Microbes.
“The bacterial intestinal pathogen Clostridioides difficile is a dreaded hospital bug particularly likely to appear in patients who have been treated with specific types of antibiotics”, explains Professor Panagiotis Papatheodorou from the Institute of Experimental and Clinical Pharmacology, Toxicology and Naturopathy at the Ulm University Medical Centre. “Since these antibiotics also kill off many useful bacteria in the intestine, the microbiome – ie the entirety of the microorganisms living there - is disrupted. This allows the pathogen to multiply unchecked in the intestine and excrete its protein toxins TcdA and TcdB”. These toxins penetrate the protective epithelial cells on the intestinal surface and damage them by inactivating important switch molecules. This causes diseases such as antibiotic-associated diarrhoea or even pseudomembranous colitis, a life-threatening inflammation of the intestine. “With severely injured trauma patients in intensive care units, C. difficile toxins can also lead to post-traumatic complications”, explains Papatheodorou, whose research focuses on cellular uptake and the mode of action of bacterial toxins.
The objective of a collaborative project with the University of Costa Rica was to pharmacologically prevent cell poisoning by C. difficile. “The weak point to be targeted for specifically inhibiting the toxins of the bacterium is their dependence on cholesterol in the cell membrane of the host cells”, says Professor Holger Barth. The head of the Institute of Experimental and Clinical Pharmacology, Toxicology and Naturopathy, who is investigating the role of bacterial toxins in the field of trauma toxicology in the Ulm CRC 1149, coordinated the study in cooperation with Professor Papatheodorou. “If we use medication to lower the cholesterol levels, TcdA and TcdB cannot enter the cells as efficiently, and the cells thus do not get poisoned”. In search of suitable active substances, the researchers applied the principle of “drug repurposing”, ie the testing of already known and licensed drugs. The advantages of this method are shorter development and authorisation periods as well as a lower risk of adverse effects.
The heart drug amiodarone has a cholesterol-reducing effect
The idea of trialling amiodarone came from Judith Schumacher, a doctoral student in medicine. “This drug is actually used to treat cardiac arrythmia”, explains Schumacher, who is pursuing her medical degree at the Institute of Experimental Clinical Pharmacology, Toxicology and Naturopathy. “My literature research showed that this drug has a cholesterol-reducing effect. So we tested out whether a pre-incubation with amiodarone could also prevent cultured cells from being poisoned with TcdA and TcdB”.
The researchers studied cultured mammalian and human cells in their experiments. Key results were verified using artificial intestinal organoids, provided by the Ulm Core Facility Organoids, which provide an alternative to animal trials for three-dimensional models of the human intestine. Using techniques of light and fluorescence microscopy, the researchers were able to make both the effect of C. difficile toxins on cultured cells and intestinal organoids and the inhibiting effect of amiodarone visible. “Our basic assumption, that amiodarone would be a potential inhibitor of TcdA and TcdB from C. difficile due to its cholesterol-reducing effect in cells was confirmed”, Schumacher relates.
The research results were recently published in Gut Microbes, the leading research journal in the field of intestinal microbiota and pathogens. According to the publication, it was discovered that amiodarone has a further mechanism for inhibiting the toxins as well. “In order to transport their toxic component into the cell interior, the toxins create a membrane pore”, explains Panagiotis Papatheodorou. “According to our data, amiodarone inhibits this process by interacting with the membrane pore directly – even with TcdA and TcdB variants from a particularly virulent and epidemic C. difficile strain”.
The increasing resistance of the bacterium to antibiotics is making the treatment of such diseases and post-traumatic complications increasingly difficult, according to the researcher. “The heart drug amiodarone could be an adjunctive therapy for C. difficile-associated illnesses, but that would need to be tested first in clinical trials”. This project received funding from the German Research Foundation (Deutsche Forschungsgemeinschaft – DFG).
Further information:
Prof Dr Panagiotis Papatheodorou, tel: 0731 / 500 65506, email: panagiotis.papatheodorou(at)uni-ulm.de
Literature reference:
Judith Schumacher, Astrid Nienhaus, Sebastian Heber, Jauheni Matylitsky, Esteban Chaves-Olarte, César Rodríguez, Holger Barth & Panagiotis Papatheodorou. Exploring the inhibitory potential of the antiarrhythmic drug amiodarone against Clostridioides difficile toxins TcdA and TcdB, in Gut Microbes, Volume 15, Issue 2, 25 Sep 2023, doi.org/10.1080/19490976.2023.2256695
Text: Anja Burkel
Mediacontact: Andrea Weber-Tuckermann
Translation: Kate Gaugler