The genetics of ivermectin resistance in Caenorhabditis elegans.
The ability of organisms to evolve resistance threatens the effectiveness of every antibiotic drug. We show that in the nematode Caenorhabditis elegans, simultaneous mutation of three genes, avr-14, avr-15, and glc-1, encoding glutamate-gated chloride channel (GluCl) alpha-type subunits confers high-level resistance to the antiparasitic drug ivermectin. In contrast, mutating any two channel genes confers modest or no resistance. We propose a model in which ivermectin sensitivity in C. elegans is mediated by genes affecting parallel genetic pathways defined by the family of GluCl genes. The sensitivity of these pathways is further modulated by unc-7, unc-9, and the Dyf (dye filling defective) genes, which alter the structure of the nervous system. Our results suggest that the evolution of drug resistance can be slowed by targeting antibiotic drugs to several members of a multigene family.
Dent
J A
JA
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. jdent@po-box.mcgill.ca
Smith
M M
MM
Vassilatis
D K
DK
Avery
L
L
D000818:Animals; D000969:Antinematodal Agents / Q000494:pharmacology*; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins; D018118:Chloride Channels / Q000235:genetics; D003001:Cloning, Molecular; D004351:Drug Resistance / Q000235:genetics*; D004594:Electrophysiology; D018698:Glutamic Acid / Q000494:pharmacology; D015801:Helminth Proteins / Q000235:genetics; D007559:Ivermectin / Q000494:pharmacology*; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D010614:Pharynx / Q000187:drug effects; D011485:Protein Binding
D000969:Antinematodal Agents; D029742:Caenorhabditis elegans Proteins; D018118:Chloride Channels; D015801:Helminth Proteins; C400274:OSM-1 protein, C elegans; C109777:glutamate-gated chloride channels; D018698:Glutamic Acid; D007559:Ivermectin