Abstract
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.
Highlights
Soil-transmitted nematodes (STNs), namely hookworms, whipworms, and ascarids, are extremely common parasites, infecting 1–2 billion of the poorest people worldwide
Soil transmitted nematodes (STNs) of humans- the giant roundworm Ascaris lumbricoides, whipworm Trichuris trichiura, and three hookworm species Necator americanus, Ancylostoma duodenale, and Ancylostoma ceylanicum –are intestinal parasites responsible for much of the morbidity associated with the neglected tropical diseases that sustain the cycle of poverty[1,2]
Since the human-parasitic hookworm A. ceylanicum can be maintained in immunocompetent hamsters, it is a relevant parasite to test as an actual human parasite in the laboratory
Summary
Soil-transmitted nematodes (STNs), namely hookworms, whipworms, and ascarids, are extremely common parasites, infecting 1–2 billion of the poorest people worldwide. Screens to date include using adult parasites in vitro[32,33], eggs hatch assay[22,34], larval-staged parasites[33,34,35], infective third stage parasitic larvae (L3i)[36,37], and the free-living nematode Caenorhabditis elegans as a surrogate[33,38,39,40,41,42] Despite these studies, little groundwork has been done to determine the comparative validity and usefulness of such screens towards finding an anthelmintic against STNs that is efficacious in vivo in laboratory models or that would be useful in human therapy. There have been little studies done regarding optimization of even a moderate throughput pipeline for gastrointestinal nematode drug discovery while focusing on or addressing the false positive and false negatives of the screening models used (e.g., the drug screens with adults above investigated at most 400 compounds)
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