Entamoeba histolytica, a protozoan intestinal parasite, is the causative agent of human
amebiasis.
Amebiasis is the fourth leading cause of death and the third leading cause of morbidity due to
protozoan infections worldwide(1), resulting in ~70,000 deaths annually. E. histolytica has been listed by the National Institutes of Health as a category B priority biodefense pathogen in the United States. Treatment relies on
metronidazole(2), which has adverse effects(3), and potential resistance of E. histolytica to the drug is an increasing concern(4,5). To facilitate drug screening for this anaerobic protozoan, we developed and validated an automated, high-throughput screen (HTS). This screen identified
auranofin, a US Food and Drug Administration (FDA)-approved drug used therapeutically for
rheumatoid arthritis, as active against E. histolytica in culture.
Auranofin was ten times more potent against E. histolytica than
metronidazole. Transcriptional profiling and
thioredoxin reductase assays suggested that
auranofin targets the E. histolytica
thioredoxin reductase, preventing the reduction of
thioredoxin and enhancing sensitivity of trophozoites to reactive
oxygen-mediated killing. In a mouse model of
amebic colitis and a hamster model of
amebic liver abscess, oral
auranofin markedly decreased the number of parasites, the detrimental host inflammatory response and hepatic damage. This new use of
auranofin represents a promising
therapy for
amebiasis, and the drug has been granted orphan-drug status from the FDA.