Ivermectin resistance and overview of the Consortium for Anthelmintic Resistance SNPs

Ivermectin (IVM) has transformed nematode parasite control in veterinary medicine and the control of some nematode infections in humans, such as onchocerciasais, lymphatic filariasis in Africa and strongyloidiasis. Unfortunately, IVM resistance is now a serious problem for parasite control in livestock and there is a concern about resistance development and spread in nematode parasites of humans. IVM is believed to act by opening glutamate-gated chloride channels and GABA-gated channels in invertebrate neurons or muscle cells, leading to hyperpolarisation of the cells and to an inhibitory paralysis. However, in the filarial nematodes, it is not altogether clear that the effect of IVM is confined to these actions or even whether these are the most important. Alterations in some ligand-gated ion channel (LGIC) receptor subunits may play a role in the mechanisms of IVM resistance in some nematodes, but the evidence that changes in LGICs are the most important cause of IVM resistance in nematodes is far from clear. What is evident is that IVM is an excellent substrate for some ATP-binding cassette transporters, IVM selects for changes in expression levels of ABC transporters, such as P-glycoproteins, and that altered levels of some ABC transporters contribute to IVM resistance. In addition, there is growing evidence that IVM selects on beta-tubulin, at least in some nematodes. Based on these various mechanisms, which contribute to IVM resistance, it may become possible to develop panels of molecular markers for IVM resistance in different nematode parasites. In order to stimulate the development of such markers, an international Consortium for Anthelmintic Resistance SNPs (CARS) has been developed to help coordinate marker development, advance our knowledge of helminth biology and possibly assist with the development of new anthelmintic molecules.