- Published
- 2023-03-02
- Venue
- PLoS Pathogens, vol. 19, no. 3, pp. e1011146
- Cited by
- 89
- Open access
- Yes, gold
- DOI
- 10.1371/journal.ppat.1011146
- PubMed
- 36862759
Abstract
Ancylostoma caninum is an important zoonotic gastrointestinal nematode of dogs worldwide and a close relative of human hookworms. We recently reported that racing greyhound dogs in the USA are infected with A. caninum that are commonly resistant to multiple anthelmintics. Benzimidazole resistance in A. caninum in greyhounds was associated with a high frequency of the canonical F167Y(TTC>TAC) isotype-1 β-tubulin mutation. In this work, we show that benzimidazole resistance is remarkably widespread in A. caninum from domestic dogs across the USA. First, we identified and showed the functional significance of a novel benzimidazole isotype-1 β-tubulin resistance mutation, Q134H(CAA>CAT). Several benzimidazole resistant A. caninum isolates from greyhounds with a low frequency of the F167Y(TTC>TAC) mutation had a high frequency of a Q134H(CAA>CAT) mutation not previously reported from any eukaryotic pathogen in the field. Structural modeling predicted that the Q134 residue is directly involved in benzimidazole drug binding and that the 134H substitution would significantly reduce binding affinity. Introduction of the Q134H substitution into the C. elegans β-tubulin gene ben-1, by CRISPR-Cas9 editing, conferred similar levels of resistance as a ben-1 null allele. Deep amplicon sequencing on A. caninum eggs from 685 hookworm positive pet dog fecal samples revealed that both mutations were widespread across the USA, with prevalences of 49.7% (overall mean frequency 54.0%) and 31.1% (overall mean frequency 16.4%) for F167Y(TTC>TAC) and Q134H(CAA>CAT), respectively. Canonical codon 198 and 200 benzimidazole resistance mutations were absent. The F167Y(TTC>TAC) mutation had a significantly higher prevalence and frequency in Western USA than in other regions, which we hypothesize is due to differences in refugia. This work has important implications for companion animal parasite control and the potential emergence of drug resistance in human hookworms.
Cite this paper
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- APA 7
Venkatesan, A., Castro, P. D. J., Morosetti, A., Horvath, H., Chen, R., Redman, E., Dunn, K., Collins, J. B., Fraser, J. S., Andersen, E. C., Kaplan, R. M., & Gilleard, J. S. (2023). Molecular evidence of widespread benzimidazole drug resistance in Ancylostoma caninum from domestic dogs throughout the USA and discovery of a novel β-tubulin benzimidazole resistance mutation. PLoS Pathogens, 19(3), e1011146. https://doi.org/10.1371/journal.ppat.1011146
- MLA 9
Venkatesan, Abhinaya, et al. "Molecular evidence of widespread benzimidazole drug resistance in Ancylostoma caninum from domestic dogs throughout the USA and discovery of a novel β-tubulin benzimidazole resistance mutation." PLoS Pathogens, vol. 19, no. 3, 2023, pp. e1011146, https://doi.org/10.1371/journal.ppat.1011146.
- Chicago
Venkatesan, Abhinaya, Pablo David Jimenez Castro, Arianna Morosetti, Hannah Horvath, Rebecca Chen, Elizabeth Redman, Kayla Dunn, et al. "Molecular evidence of widespread benzimidazole drug resistance in Ancylostoma caninum from domestic dogs throughout the USA and discovery of a novel β-tubulin benzimidazole resistance mutation." PLoS Pathogens 19, no. 3 (2023): e1011146. https://doi.org/10.1371/journal.ppat.1011146.
- GOST
Venkatesan A., Castro P. D. J., Morosetti A. [и др.] Molecular evidence of widespread benzimidazole drug resistance in Ancylostoma caninum from domestic dogs throughout the USA and discovery of a novel β-tubulin benzimidazole resistance mutation // PLoS Pathogens. — 2023. — Vol. 19, № 3. — P. e1011146. — URL: https://doi.org/10.1371/journal.ppat.1011146
- BibTeX
@article{venkatesan2023molecular, title = {{Molecular evidence of widespread benzimidazole drug resistance in Ancylostoma caninum from domestic dogs throughout the USA and discovery of a novel β-tubulin benzimidazole resistance mutation}}, author = {Abhinaya Venkatesan and Pablo David Jimenez Castro and Arianna Morosetti and Hannah Horvath and Rebecca Chen and Elizabeth Redman and Kayla Dunn and James Bryant Collins and James S. Fraser and Erik C. Andersen and Ray M. Kaplan and John S. Gilleard}, journal = {PLoS Pathogens}, year = {2023}, volume = {19}, number = {3}, pages = {e1011146}, doi = {10.1371/journal.ppat.1011146}, url = {https://doi.org/10.1371/journal.ppat.1011146} }- RIS
TY - JOUR AU - Venkatesan, Abhinaya AU - Castro, Pablo David Jimenez AU - Morosetti, Arianna AU - Horvath, Hannah AU - Chen, Rebecca AU - Redman, Elizabeth AU - Dunn, Kayla AU - Collins, James Bryant AU - Fraser, James S. AU - Andersen, Erik C. AU - Kaplan, Ray M. AU - Gilleard, John S. TI - Molecular evidence of widespread benzimidazole drug resistance in Ancylostoma caninum from domestic dogs throughout the USA and discovery of a novel β-tubulin benzimidazole resistance mutation JO - PLoS Pathogens VL - 19 IS - 3 SP - e1011146 PY - 2023 DA - 2023/03/02 DO - 10.1371/journal.ppat.1011146 UR - https://doi.org/10.1371/journal.ppat.1011146 ER -
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