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Soil-transmitted nematodes (STNs), namely hookworms, whipworms, and ascarids, are extremely common parasites, infecting 1–2 billion of the poorest people worldwide. Two benzimidazoles, albendazole and mebendazole, are currently used in STN mass drug administration, with many instances of low/reduced activity reported. New drugs against STNs are urgently needed. We tested various models for STN drug screening with the aim of identifying the most effective tactics for the discovery of potent, safe and broad-spectrum agents. We screened a 1280-compound library of approved drugs to completion against late larval/adult stages and egg/larval stages of both the human hookworm parasite  Ancylostoma ceylanicum  and the free-living nematode  Caenorhabditis elegans , which is often used as a surrogate for STNs in screens. The quality of positives was further evaluated based on cheminformatics/data mining analyses and activity against evolutionarily distant  Trichuris muris  whipworm adults. From these data, two pairs of positives, sulconazole/econazole and pararosaniline/cetylpyridinium, predicted to target nematode CYP-450 and HSP-90 respectively, were prioritized for  in vivo  evaluation against  A .  ceylanicum  infections in hamsters. One of these positives, pararosaniline, showed a significant impact on hookworm fecundity  in vivo . Taken together, our results suggest that anthelmintic screening with  A .  ceylanicum  larval stages is superior to  C .  elegans  based on both reduced false negative rate and superior overall quality of actives. Our results also highlight two potentially important targets for the discovery of broad-spectrum human STN drugs.

Drug Screening for Discovery of Broad-spectrum Agents for Soil-transmitted Nematodes