Nat. Med., published online 20 May 2012, doi:10.1038/nm.2758

Entamoeba histolytica, an intestinal protozoan parasite, is the causative agent of the life-threatening infection amebiasis. Debnath et al. now identify auranofin, a US Food and Drug Administration-approved drug, as a potent inhibitor of E. histolytica growth. The authors screened the 910-member Iconix library and identified 11 compounds with strong amoebicidal activities, with auranofin being the most potent of all. Although auranofin has been clinically used for treating rheumatoid arthritis for years, its mode of action has remained elusive. To gain insight into the molecular mechanism, the authors compared the gene expression signatures of untreated and auranofin-treated parasites. The arsenite-inducible RNA-associated protein transcript was significantly upregulated in auranofin-treated parasites, leading the authors to hypothesize that arsenite and auranofin target the same protein in E. histolytica. Previous work had suggested that both arsenite and auranofin inhibit thioredoxin reductase (TrxR), an enzyme involved in reactive oxygen species detoxification. The authors showed that auranofin could inhibit the enzymatic activity of recombinant E. histolytica TrxR in vitro, whereas in vivo auranofin rendered the trophozoites highly susceptible to H2O2. Also, the drug inhibited the infection in rodent models of amebiasis. In sum, the authors, by screening a high-throughput library, repurposed auranofin and showed that it can target the growth of E. histolytica and could potentially be used in treating amebiasis.