Identification of anisomycin, prodigiosin and obatoclax as compounds with broad-spectrum anti-parasitic activity

Abstract

Parasitic infections are a major source of human suffering, mortality, and economic loss, but drug development for these diseases has been stymied by the significant expense involved in bringing a drug though clinical trials and to market. Identification of single compounds active against multiple parasitic pathogens could improve the economic incentives for drug development as well as simplifying treatment regimens. We recently performed a screen of repurposed compounds against the protozoan parasite Entamoeba histolytica, causative agent of amebic dysentery, and identified four compounds (anisomycin, prodigiosin, obatoclax and nithiamide) with low micromolar potency and drug-like properties. Here, we extend our investigation of these drugs. We assayed the speed of killing of E. histolytica trophozoites and found that all four have more rapid action than the current drug of choice, metronidazole. We further established a multi-institute collaboration to determine whether these compounds may have efficacy against other parasites and opportunistic pathogens. We found that anisomycin, prodigiosin and obatoclax all have broad-spectrum antiparasitic activity in vitro, including activity against schistosomes, T. brucei, and apicomplexan parasites. In several cases, the drugs were found to have significant improvements over existing drugs. For instance, both obatoclax and prodigiosin were more efficacious at inhibiting the juvenile form of Schistosoma than the current standard of care, praziquantel. Additionally, low micromolar potencies were observed against pathogenic free-living amebae (Naegleria fowleri, Balamuthia mandrillaris and Acanthamoeba castellanii), which cause CNS infection and for which there are currently no reliable treatments. These results, combined with the previous human use of three of these drugs (obatoclax, anisomycin and nithiamide), support the idea that these compounds could serve as the basis for the development of broad-spectrum anti-parasitic drugs. Parasitic diseases are a major cause of human morbidity and mortality worldwide, as well as a significant economic drain in developing countries. Many parasites have limited treatment options with low efficacy and significant side effects, however research into new therapeutics suffers from a lack of investment. In this study, we characterize four potential anti-parasitic drugs: anisomycin, nithiamide, prodigiosin and obatoclax. These drugs were previously shown to effectively inhibit Entamoeba histolytica, the parasite that causes amebic dysentery. Here, we demonstrate that these drugs have activity against a wide variety of parasites from different taxonomic groups. Additionally, we assessed the speed of killing of these compounds against E. histolytica and the brain pathogen Balamuthia mandrillaris, and show that several are faster acting than current drugs. Two of these drugs (prodigiosin and obatoclax) had broad-spectrum activity, including against life stages not treated by current drugs such as juvenile schistosome worms, and three (obatoclax, nithiamide and anisomycin) have been used previously in humans. Although more study will be needed to adapt these drugs to the varying requirements for treatment of each parasitic disease, this work is a promising beginning towards identifying drugs against multiple parasites that are human pathogens.