The effects of amidantel (BAY d 8815) and its deacylated derivative (BAY d 9216) on wild-type and resistant mutants of Caenorhabditis elegans
The anthelmintic drugs amidantel (BAY d 8815) and its deacylated derivative (BAY d 9216) inhibited the growth of wild-type (N2) Caenorhabditis elegans but had little effect on development or reproductive capacity. Inhibition of growth correlated well with drug-induced paralysis, both becoming maximal at around 1.0 mM concentration of either drug. Egg laying was delayed by about 24 h and the rate of laying was only about 60–70% of the controls. However, the period during which eggs were laid was extended by a similar amount and the total number of eggs laid was the same for controls and drug-treated worms. Five drug-resistant mutants (T114, T22, T26, T216, and T226) were isolated following ethylmethanesulphonate mutagenesis. All were shorter than N2 at 96 h on drug-free medium; their growth was not further impaired by either of the anthelmintic drugs. All except T114 exhibited a normal pattern of sexual maturation. Cultures of T114 at 96 h contained many immature worms. This mutant also exhibited the most impaired motility, being severely uncoordinated in liquid suspension. The other mutants could swim normally but were noticeably slower than N2. Genetic analysis indicated that each mutant was the result of a single genetic lesion, that the mutants were recessive, and that there were two genes for amidantel resistance (adt1 and adt2). In vitro studies on representatives of each class (T114 and T22) indicated a defect in the acetylcholine receptor. T22 mutants showed a moderate decrease in sensitivity towards typical cholinergic agonists as well as the anthelmintic drugs, while T114 mutants were apparently devoid of functional pharmacological acetylcholine receptors.