Study Investigates Amiodarone As a Potential Toxin Inhibitor for Clostridioides difficile Infections

A recent in vitro study published in Gut Microbes explored using amiodarone as a potential toxin inhibitor for Clostridioides difficile infections. The study showed that amiodarone decreased the cholesterol in cell membranes, an essential factor in C. difficile toxins’ ability to enter cells.

Infection with the human pathogen C. difficile can cause antibiotic-associated diarrhea and pseudomembranous colitis, which are C. difficile-associated diseases (CDADs).

The pathogen C. difficile releases the toxins TcdA and TcdB, which cause the symptoms associated with CDADs. The toxins cause cell destruction by entering the host cell and inactivating proteins Rho and Ras GTPases, which are essential in developing the cell’s cytoskeleton.

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TcdA and TcdB enter human cells through endocytosis, and the endosome that encapsulates the toxins then forms a pore so the toxins can move into the host cell. The cell membrane depends on cholesterol to complete endocytosis and pore formation.

Recent investigations have shown amiodarone decreases cholesterol biosynthesis by inhibiting the enzyme 24-dehydrocholesterol reductase.

Related studies have shown the cholesterol-decreasing effect of amiodarone to have an antiviral effect against SARS-CoV-2 and inhibit bacterial toxins from diphtheria and anthrax. The authors of this new study hypothesized that amiodarone could block C. difficile toxins from entering host cells by decreasing cholesterol in cell membranes.

This lab study showed that when human gut cells were preincubated with amiodarone before introducing C. difficile pathogens, it protected the cells against the individual toxins TcdA and TcdB, the combination of both, and several pathogen variants, including the epidemic C. difficile strain NAP1/027.

The study used concentrations of amiodarone recommended for use with cardiac indications.Long-term use of amiodarone is associated with an increased risk of severe adverse effects.Amiodarone for CDADs would only be used for short term and, as a topical, rectal administration, which would minimize the risks associated with its use.

The results of this study indicate that the cholesterol-lowering effects of amiodarone could be a target for toxin control in C. difficile infections. Amiodarone also provides pan-variant protection against toxins, a potentially growing area of research in C. difficile infection treatment.

Reference

Schumacher J, Nienhaus A, Heber S, et al. Exploring the inhibitory potential of the antiarrhythmic drug amiodarone against Clostridioides difficile toxins TcdA and TcdB. Gut Microbes. 2023;15(2):2256695. doi:10.1080/19490976.2023.2256695