The genetics of ivermectin resistance in Caenorhabditis elegans

The ability of organisms to evolve resistance threatens the effectiveness o f every antibiotic drug. We show that in the nematode Caenorhabditis elegan s, simultaneous mutation of three genes, avr-14, avr-15, and glc-1, encodin g glutamate-gated chloride channel (GIuCl) alpha-type subunits confers high -level resistance to the antiparasitic drug ivermectin, In contrast, mutati ng any two channel genes confers modest or no resistance. We propose a mode l in which ivermectin sensitivity in C. elegans is mediated by genes affect ing parallel genetic pathways defined by the family of GluCl genes. The sen sitivity of these pathways is further modulated by unc-7, unc-9, and the Dy f (dye filling defective) genes, which alter the structure of the nervous s ystem. Our results suggest that the evolution of drug resistance can be slo wed by targeting antibiotic drugs to several members of a multigene family.