The functions of nine ATP-binding cassette (ABC) transporter genes,
mrp-1,
mrp-4,
mrp-6,
pgp-2,
pgp-3,
pgp-4,
pgp-5,
haf-2 and
haf-9, in an ivermectin (IVM) resistant strain of Caenorhabditis elegans were screened by comparing transcription levels between the resistant (IVR10) and wild-type (Bristol N2) strains, and by measuring the effects of RNA interference (RNAi) on the IVM resistant strain, on motility, pharyngeal pumping, egg production and death in the presence or varying concentrations of IVM (0-20 ng/ml). mRNA levels of
mrp-1, 2, 4, 5, 6, 7,
pgp-1, 2, 4, 12, 14,
haf-1, 2 and 3 were significantly increased in IVR10 compared with the N2 strain. At 15 or 20 ng/ml IVM, down regulation of
mrp-1,
pgp-4,
haf-2 and
haf-9 significantly increased the effect of IVM to reduce egg production. At low to moderate IVM concentrations, down regulation of
mrp-1 and
haf-2 reduced the motility of C. elegans. However, at high IVM concentrations motility was increased by down regulation of transcription of
pgp-3,
pgp-4 and
haf-9. Down regulation of expression of
mrp-1,
pgp-2 and
pgp-5 resulted in reduced pharyngeal pumping in the presence of varying concentrations of IVM, while down regulation of
mrp-6 and
haf-2 increased pharyngeal pumping of the resistant strain irrespective of the IVM concentration used. Although the IVR10 strain was markedly resistant to IVM, compared with the unselected N2 strain, IVM led to the death of the C. elegans in a concentration dependent manner. However, differences in the IVM induced death rate, following RNAi, were not significantly different from the IVR10 strain without RNAi. The study shows that different ABC transporter genes may play a role in modulating the effects of IVM on pharyngeal pumping, motility and egg production, with down regulation of
mrp-1 and
haf-2 perhaps having the greatest effects. However, down regulation of expression of no individual ABC transporter gene profoundly affected the effect of IVM on mortality in the IVR10 strain. This suggests that some of these ABC transporter genes and their products may play a role in modulating the effects of IVM, but are not, individually, the critical gene responsible for IVM resistance. This study provides a model that may help to understand drug resistance in parasitic nematodes.