Pro-Survival Pathway Protects from C. difficile Toxin-Mediated Cell Death.

There is an urgent need for new non-antibiotic based treatment strategies for Clostridioides difficile infection. C. difficile toxin B (TcdB) is a virulent factor that is essential for causing disease. Here, we investigated whether a survival-signaling pathway could protect against TcdB. We found significant increase in caspase-3 apoptotic activity in intestinal epithelial cells of mice exposed to TcdB. Subsequently, activation of the MIF-CD74-Akt pro-survival signaling pathway blocked TcdB-induced caspase-3 activity and intestinal epithelial cell death. This brief report provides proof-of-concept that targeting pro-survival pathways may represent a unique antibiotic-independent strategy for protecting against C. difficile toxin-mediated cell death.

Alcohol Abuse Drug Disulfiram Is Effective against Cyst Stages of Entamoeba histolytica Parasite.

New anti-Entamoeba histolytica multistage drugs are needed because only one drug class, nitroimidazoles, is available for treating invasive disease, and it does not effectively eradicate the infective cyst stage. Zinc ditiocarb (ZnDTC), a main metabolite of the FDA-approved drug disulfiram, was recently shown to be highly effective against the invasive trophozoite stage. In this brief report, we show that ZnDTC is active against cysts, with similar potency to first-line cysticidal drug paromomycin.

Drug Repurposing of the Alcohol Abuse Medication Disulfiram as an Anti-Parasitic Agent.

Parasitic infections contribute significantly to worldwide morbidity and mortality. Antibiotic treatment is essential for managing patients infected with these parasites since control is otherwise challenging and there are no vaccines available for prevention. However, new antimicrobial therapies are urgently needed as significant problems exist with current treatments such as drug resistance, limited options, poor efficacy, as well as toxicity. This situation is made worse by the challenges of drug discovery and development which is costly especially for non-profitable infectious diseases, time-consuming, and risky with a high failure rate. Drug repurposing which involves finding new use for existing drugs may help to more rapidly identify therapeutic candidates while drastically cutting costs of drug research and development. In this perspective article, we discuss the importance of drug repurposing, review disulfiram pharmacology, and highlight emerging data that supports repurposing disulfiram as an anti-parasitic, exemplified by the major diarrhea-causing parasite Entamoeba histolytica.