A study shows that it is worth exploring what else existing medications can do: Researchers have found that a well-known heart medication can protect against the toxins of a notorious pathogen that causes intestinal inflammation. The results give hope that the active ingredient amiodarone could protect weakened patients from dangerous antibiotic-associated diarrhea and intestinal inflammation caused by the pathogen Clostridioides difficile in the future, say the scientists.
Due to the large number of sick people, certain treatment procedures and the massive use of antibiotics, they can thrive in clinical environments and develop more and more potential for danger: keeping the so-called hospital germs in check presents modern medicine with enormous challenges. The intestinal bacterium Clostridioides difficile is considered one of the worst representatives of these microbes. It becomes a problem especially after antibiotic treatments. In addition to the actual treatment goals, the beneficial microbes in our intestines are also killed. C. difficile can often use the opportunity for recolonization particularly efficiently - with dire consequences.
Stubborn poisoners in the intestines
“This pathogen can then multiply unhindered and secretes its protein toxins TcdA and TcdB,” explains senior author Panagiotis Papatheodorou from the Ulm University Hospital. As is well known, these poisons can then have fatal effects: They cause so-called antibiotic-associated diarrhea or, in the worst case, pseudomembranous colitis, a life-threatening intestinal inflammation. The C. difficile toxins therefore pose a great danger to patients who are already weakened, for example in intensive care units. However, so far there are hardly any options for treatment and the bacterium is also developing more and more resistance to common antibiotics. That's why Papatheodorou and his team have dedicated themselves to finding new approaches to combat the clinical problem.
Specifically, the aim was to pharmacologically prevent cell poisoning by C. difficile. Instead of developing completely new active ingredients, the researchers explored the potential of repurposing – so-called drug repurposing. This approach is used when a possible target is already known that could be attacked by drugs that have already been developed. “Their dependence on cholesterol in the membranes of the host cells appeared to be a suitable target for specifically inhibiting the toxins of C. difficile,” says co-author Holger Barth from the Ulm University Hospital. It is known that TcdA and TcdB enter victims via this fatty substance. The idea is that if you lower the cholesterol level with medication, poisoning could be avoided. That's why the scientists started looking for potentially suitable active ingredients among the known drugs that affect cholesterol.
Successful drug repurposing
The active ingredient amiodarone turned out to be a hit. “It is actually used as an antiarrhythmic drug to treat cardiac arrhythmias,” explains first author Judith Schumacher from Ulm University Hospital. “However, the literature research showed that amiodarone has a specific cholesterol-lowering effect. We therefore tested whether pre-incubation with amiodarone could also protect cultured cells from poisoning with TcdA and TcdB,” reports the researcher. The team first carried out experiments on mammalian and human cells cultured in the laboratory. When the results showed promising results, they also moved on to tests on three-dimensional models of the human intestine grown in the laboratory. Using these organoids, the researchers were then able to examine in detail the cellular effect of the poisons and the effect of the promising active ingredient.
“Our basic assumption that amiodarone can be used as an inhibitor of TcdA and TcdB from C. difficile due to its cholesterol-lowering effect in cells was confirmed,” says Schumacher. By reducing the cholesterol content in the cell membranes, it was possible to prevent toxic amounts of toxins from causing internal destruction. The team also found that amiodarone inhibits the toxins via another mechanism. “In order to transport their toxic portion into the interior of the cell, the toxins form a membrane pore,” explains Papatheodorou. “According to our data, amiodarone inhibits this process by interacting directly with this membrane pore - even with TcdA and TcdB variants from a particularly virulent and epidemic C. difficile strain,” says the scientist.
The team now sees considerable potential for the active ingredient in the treatment of the dreaded infections with the toxic pathogen. The central advantage of drug repurposing can now also come into play: shorter development and approval times and a lower risk of undesirable effects. “Initially, clinical studies on the effect are still necessary. “But it seems possible that the heart drug amiodarone is suitable for adjunctive therapy in C. difficile-associated diseases,” says Papatheodorou.
Source: Ulm University, specialist article: Gut Microbes, doi: 10.1080/19490976.2023.2256695