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PMID:10716995

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Citation

Dent, JA, Smith, MM, Vassilatis, DK and Avery, L (2000) The genetics of ivermectin resistance in Caenorhabditis elegans. Proc. Natl. Acad. Sci. U.S.A. 97:2674-9

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.

Links

PubMed PMC15988

Keywords

Animals; Antinematodal Agents/pharmacology; Caenorhabditis elegans/drug effects; Caenorhabditis elegans/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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

CAEEL:Q8IFY7

located_in

GO:0016020: membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

CAEEL:Q8IFY7

involved_in

GO:0006811: ion transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:Q8IFY7

enables

GO:0008068: extracellularly glutamate-gated chloride channel activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

CAEEL:Q8IFY7

involved_in

GO:0042493: response to drug

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000233
WB:WBGene00001591
WB:WBGene00006747

P

Seeded From UniProt

complete

CAEEL:Q8IFY7

involved_in

GO:0042493: response to drug

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000233
WB:WBGene00006747

P

Seeded From UniProt

complete

CAEEL:Q8IFY7

involved_in

GO:0042493: response to drug

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000233
WB:WBGene00001591

P

Seeded From UniProt

complete

CAEEL:Q8IFY7

involved_in

GO:0042493: response to drug

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000233

P

Seeded From UniProt

complete

CAEEL:Q95Q96

located_in

GO:0016020: membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

CAEEL:Q95Q96

involved_in

GO:0006811: ion transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:Q95Q96

enables

GO:0008068: extracellularly glutamate-gated chloride channel activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

CAEEL:Q95Q96

involved_in

GO:0042493: response to drug

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000233
WB:WBGene00001591
WB:WBGene00006747

P

Seeded From UniProt

complete

CAEEL:Q95Q96

involved_in

GO:0042493: response to drug

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000233
WB:WBGene00006747

P

Seeded From UniProt

complete

CAEEL:Q95Q96

involved_in

GO:0042493: response to drug

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000233
WB:WBGene00001591

P

Seeded From UniProt

complete

CAEEL:Q95Q96

involved_in

GO:0042493: response to drug

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000233

P

Seeded From UniProt

complete

CAEEL:Q95Q97

located_in

GO:0016020: membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

CAEEL:Q95Q97

involved_in

GO:0006811: ion transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:Q95Q97

enables

GO:0008068: extracellularly glutamate-gated chloride channel activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

CAEEL:Q95Q97

involved_in

GO:0042493: response to drug

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000233
WB:WBGene00001591
WB:WBGene00006747

P

Seeded From UniProt

complete

CAEEL:Q95Q97

involved_in

GO:0042493: response to drug

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000233
WB:WBGene00006747

P

Seeded From UniProt

complete

CAEEL:Q95Q97

involved_in

GO:0042493: response to drug

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000233
WB:WBGene00001591

P

Seeded From UniProt

complete

CAEEL:Q95Q97

involved_in

GO:0042493: response to drug

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000233

P

Seeded From UniProt

complete


See also

References

See Help:References for how to manage references in GONUTS.