Abstract
BackgroundParasitic worms represent a substantial disease burden in animals and humans worldwide. The control of parasitic roundworms (nematodes) relies heavily on the use of anthelmintic drugs. However, widespread drug resistance in nematodes seriously compromises the effectiveness of many anthelmintics around the world. Thus, there is a need to discover new drugs, with unique modes of action, against parasites.MethodsHere, we synthesised and tested 74 selective estrogen receptor modulators (SERMs) for in vitro-activity on parasitic larvae of Haemonchus contortus (barber’s pole worm), one of the most important nematode pathogens of small ruminants (including sheep and goats) and a key representative of one of the largest groups of parasitic nematodes (the Strongylida) of animals. We also studied the morphology of treated and untreated larvae using scanning electron microscopy (SEM), and assessed the agonistic/antagonistic activity of SERMs in a human embryonic kidney cell line using a luciferase reporter assay system.ResultsWe identified three SERMs (one selenophene and two thiophene-core compounds) with potent inhibitory activities (at 3–25 μM) on the motility and development of parasitic stages of H. contortus. An SEM examination of treated H. contortus revealed considerable damage to the cuticle of fourth- but not exsheathed, third-stage larvae; this damage appeared to be consistent with that observed upon treatment with monepantel but not moxidectin (control compounds).ConclusionThe potency of the three SERMs compared favourably with commercially available anthelmintics, such that they warrant further assessment as nematocides. Future studies could focus on assessing the selectivity of these SERMs to parasites, characterising their target(s) and/or designing analogs that are parasite-specific.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-016-1612-4) contains supplementary material, which is available to authorized users.
Highlights
Parasitic worms represent a substantial disease burden in animals and humans worldwide
It is transmitted orally from contaminated pasture to the host through a direct life-cycle [3]: eggs are excreted in host faeces; the first-stage larvae (L1s) develop inside eggs to hatch and develop through to the second (L2)and third (L3)-stage larvae in about a week; infective L3s are ingested by the host, exsheath and, after a histotropic phase, develop through fourth (L4)-stage larvae to dioecious adults in the abomasum
In public-private and cross-disciplinary partnerships, we have developed an efficient whole-organism drugscreening assay for H. contortus for the discovery and subsequent repurposing of compounds to parasitic nematodes [14,15,16]
Summary
Parasitic worms represent a substantial disease burden in animals and humans worldwide. Haemonchus contortus (the barber’s pole worm) is a highly significant pathogen of livestock worldwide, affecting hundreds of millions of small ruminants (including sheep and goats) and causing economic losses [1, 2] estimated at tens of billions of dollars per annum. This parasite feeds on blood in the stomach (abomasum) and causes gastritis, anaemia and associated complications as well as mortality. It is transmitted orally from contaminated pasture to the host through a direct life-cycle [3]: eggs are excreted in host faeces; the first-stage larvae (L1s) develop inside eggs to hatch (usually within one day) and develop through to the second (L2)and third (L3)-stage larvae in about a week; infective L3s are ingested by the host, exsheath (xL3) and, after a histotropic phase, develop through fourth (L4)-stage larvae to dioecious adults (within three weeks) in the abomasum
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