The pathogen Clostridioides difficile (C. difficile) is naturally present in the intestines of many people. When present in small numbers, it usually causes no symptoms. Treatment with broad-spectrum antibiotics can severely disrupt the balance of the healthy gut microbiome, allowing the bacterium to multiply unrestricted. The result is acute intestinal inflammation, which can also become chronic. Such infections with C. difficile (CDI) are one of the leading causes of antibiotic-associated diarrhea. Since the bacteria release toxins that can lead to dangerous, sometimes life-threatening intestinal inflammation with high relapse rates, new therapeutic approaches are urgently needed. A research team led by HIPS Department Head and Scientific Director Prof. Rolf Müller has now identified a drug candidate that specifically kills C. difficile while sparing large parts of the microbiome. HIPS is a site of the Helmholtz Centre for Infection Research (HZI) in collaboration with Saarland University.
“We were able to show that the natural compound argyrin B is highly effective against CDI: both in laboratory experiments and in a mouse model of the infection, where it significantly reduces the bacterial load,” says Dr. Jennifer Herrmann, senior scientist in the department “Microbial Natural Products” at HIPS. “An antibacterial target of the argyrins had previously been identified and characterized in the notorious hospital-acquired pathogen Pseudomonas aeruginosa. Now we have been able to show that argyrin B also acts on this target in C. difficile and exhibits particularly high efficacy in doing so. In contrast, the argyrins have virtually no effect on the beneficial microorganisms in our digestive tract. The gut microbiome could therefore be spared during treatment with argyrin and restored to a healthy state more quickly.”
The argyrins were identified in soil-dwelling myxobacteria. These bacteria use such natural compounds, among other things, to hunt other microorganisms and exploit them as a food source. However, before argyrins can be used as medications, not only their efficacy but also the pharmaceutical properties of this class of substances must be evaluated. In doing so, the researchers discovered that argyrin B barely enters the bloodstream of mice when administered orally. Instead, it remains largely in the large intestine. This also helps prevent unwanted side effects in other parts of the body. Argyrin B therefore represents a potentially well-tolerated therapeutic approach against CDI.
Fecal microbiota transfer (commonly known as a stool transplant) is often used to treat CDI in cases of multiple relapses. However, this procedure is complex and unpleasant for many patients. A new active ingredient based on argyrin could help reduce the risk of further disruptions to the gut microbiota, infections, and relapses that would otherwise require treatment via microbiota transfer. In follow-up studies, the researchers aim to determine the optimal dosage of argyrin B required to achieve maximum efficacy. They also plan to use appropriate models to test how effective this natural compound is against recurrent infections.
