Home LiteratureArticle Details
PMID: 10716995 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

The genetics of ivermectin resistance in Caenorhabditis elegans.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 97 ·No. 6 ·2000-03-14 ·Pages 2674-9

Dent JA, Smith MM, Vassilatis DK, Avery L

Abstract

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.

MeSH Terms
Animals Antinematodal Agents/pharmacology Caenorhabditis elegans/drug effects,genetics Caenorhabditis elegans Proteins Chloride Channels/genetics Cloning, Molecular Drug Resistance/genetics Electrophysiology Glutamic Acid/pharmacology Helminth Proteins/genetics Ivermectin/pharmacology Models, Biological Models, Genetic Mutation Pharynx/drug effects Protein Binding
Chemicals
Antinematodal Agents Caenorhabditis elegans Proteins Chloride Channels Helminth Proteins OSM-1 protein, C elegans glutamate-gated chloride channels Glutamic Acid Ivermectin
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Dent J A
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. jdent@po-box.mcgill.ca
Smith M M
Vassilatis D K
Avery L
References (29)
29 references, click to expand
  1. Ivermectin resistance.
    Parasitol Today. 1993 May;9(5):154-9 PMID: 15463742
  2. The pharynx of Caenorhabditis elegans.
    Philos Trans R Soc Lond B Biol Sci. 1976 Aug 10;275(938):299-325 PMID: 8805
  3. Genetic differences affecting the potency of stereoisomers of halothane.
    Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):10054-8 PMID: 7937836
  4. An electrophysiological preparation of Ascaris suum pharyngeal muscle reveals a glutamate-gated chloride channel sensitive to the avermectin analogue, milbemycin D.
    Parasitology. 1996 Feb;112 ( Pt 2):247-52 PMID: 8851865
  5. Anthelmintic resistance.
    Vet Parasitol. 1994 Aug;54(1-3):259-68 PMID: 7846855
  6. Identification and functional expression of a novel ligand binding subunit of the inhibitory glycine receptor.
    J Biol Chem. 1990 Dec 25;265(36):22317-20 PMID: 2176214
  7. Mutagenesis.
    Methods Cell Biol. 1995;48:31-58 PMID: 8531732
  8. Genetic pharmacology: interactions between drugs and gene products in Caenorhabditis elegans.
    Methods Cell Biol. 1995;48:187-204 PMID: 8531725
  9. Alternative splicing of a Caenorhabditis elegans gene produces two novel inhibitory amino acid receptor subunits with identical ligand binding domains but different ion channels.
    Gene. 1997 Nov 12;201(1-2):119-25 PMID: 9409779
  10. Efficient gene transfer in C.elegans: extrachromosomal maintenance and integration of transforming sequences.
    EMBO J. 1991 Dec;10(12):3959-70 PMID: 1935914
  11. Drosophila Shaking-B protein forms gap junctions in paired Xenopus oocytes.
    Nature. 1998 Jan 8;391(6663):181-4 PMID: 9428764
  12. Interaction of GABA and volatile anesthetics in the nematode Caenorhabditis elegans.
    FASEB J. 1990 May;4(8):2506-10 PMID: 2335273
  13. Cloning of an avermectin-sensitive glutamate-gated chloride channel from Caenorhabditis elegans.
    Nature. 1994 Oct 20;371(6499):707-11 PMID: 7935817
  14. Avermectin binding in Caenorhabditis elegans. A two-state model for the avermectin binding site.
    Biochem Pharmacol. 1989 Jul 15;38(14):2329-38 PMID: 2751697
  15. Anthelmintic resistance: past, present and future.
    Int J Parasitol. 1999 Jan;29(1):115-24; discussion 137-8 PMID: 10048824
  16. avr-15 encodes a chloride channel subunit that mediates inhibitory glutamatergic neurotransmission and ivermectin sensitivity in Caenorhabditis elegans.
    EMBO J. 1997 Oct 1;16(19):5867-79 PMID: 9312045
  17. Mutations affecting the chemosensory neurons of Caenorhabditis elegans.
    Genetics. 1995 Jan;139(1):171-88 PMID: 7705621
  18. Anthelmintics and ion-channels: after a puncture, use a patch.
    Int J Parasitol. 1998 Jun;28(6):849-62 PMID: 9673865
  19. Pharmacology of anthelmintic resistance.
    Parasitology. 1996;113 Suppl:S201-16 PMID: 9051936
  20. eat-5 and unc-7 represent a multigene family in Caenorhabditis elegans involved in cell-cell coupling.
    J Cell Biol. 1996 Jul;134(2):537-48 PMID: 8707836
  21. Genetic and biochemical evidence for a novel avermectin-sensitive chloride channel in Caenorhabditis elegans. Isolation and characterization.
    J Biol Chem. 1997 Dec 26;272(52):33167-74 PMID: 9407104
  22. The Caenorhabditis elegans avermectin resistance and anesthetic response gene unc-9 encodes a member of a protein family implicated in electrical coupling of excitable cells.
    J Neurochem. 1997 Dec;69(6):2251-60 PMID: 9375655
  23. Sequence and expression of a novel GABAA receptor alpha subunit.
    FEBS Lett. 1989 Nov 20;258(1):119-22 PMID: 2556293
  24. Pharyngeal pumping continues after laser killing of the pharyngeal nervous system of C. elegans.
    Neuron. 1989 Oct;3(4):473-85 PMID: 2642006
  25. Haemonchus contortus: selection at a glutamate-gated chloride channel gene in ivermectin- and moxidectin-selected strains.
    Exp Parasitol. 1998 Sep;90(1):42-8 PMID: 9709029
  26. Effects of starvation and neuroactive drugs on feeding in Caenorhabditis elegans.
    J Exp Zool. 1990 Mar;253(3):263-70 PMID: 2181052
  27. The mechanism of action of avermectins in Caenorhabditis elegans: correlation between activation of glutamate-sensitive chloride current, membrane binding, and biological activity.
    J Parasitol. 1995 Apr;81(2):286-94 PMID: 7707209
  28. Haemonchus contortus: ivermectin-induced paralysis of the pharynx.
    Exp Parasitol. 1993 Aug;77(1):88-96 PMID: 8344410
  29. Assembly of the inhibitory glycine receptor: identification of amino acid sequence motifs governing subunit stoichiometry.
    Neuron. 1993 Dec;11(6):1049-56 PMID: 8274276
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.97.6.2674
Email
jdent@po-box.mcgill.ca
Published
2000-03-14
Pages
2674-9
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC15988
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.97.6.2674 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2