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 PLOS NEGLECTED TROPICAL DISEASES

Tambjamines and Prodiginines: Biocidal Activity against Trypanosoma cruzi

“…Obatoclax displayed remarkable trypanocidal activity against the epimastigotes of T. cruzi ; however, its effectiveness against the intracellular forms of T. cruzi was slightly lower than that of the other molecules assayed. This is consistent with the results recently reported by Ehrenkaufer et al, who demonstrated that Obatoclax had remarkable activities against Entamoeba , Giardia , and Trypanosoma brucei , with IC 50 values of 0.5, 0.9, and 0.04 µM, respectively [ 34 ]. Here, we provide the effectiveness data of this compound in T. cruzi .…”

“…Therefore, they should be, in principle, resistant to Obatoclax unless the mode of action of Obatoclax involves some more targets than the inhibition of this apoptotic regulator. Ehrenkaufer et al [ 34 ] reported that other Bcl-2 inhibitors such as venetoclax, navitoclax, A-1331852, A-1210477, and S63845 do not have an effect on the viability of different parasites, subsequently suggesting that a different mechanism of action should be investigated. Their results clearly indicated that Obatoclax most likely kills the parasites through a BCL-2-independent mechanism.…”

TriTOX: A novel Trichomonas vaginalis assay platform for high-throughput screening of compound libraries

“…Of the 11 compounds that were not part of a larger structural class, anisomycin had been previously reported in other screens to have broad-spectrum anti-parasitic activity in at least 3 other parasite species ( Ehrenkaufer et al, 2020 ; Sears and O'Hare, 1988 ). Anisomycin is proposed to inhibit protein synthesis specifically in eukaryotic cells, blocking peptide bond formation on eukaryotic ribosomes ( Jimenez and Vázquez, 1979 ).…”

Drug Discovery against Acanthamoeba Infections: Present Knowledge and Unmet Needs

“…In addition, the most effective combination that inhibited the parasite growth with limited cytotoxicity was 17.6% Diclofenaco-lepori and 82.4% atorvastatin [84]. Another study reported low EC 50 values for prodigiosin (2.2 µM) and obatoclax (0.5 µM) against A. castellanii trophozoites [85].…”