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Isolation and characterization of a naturally occurring multidrug-resistant strain of the canine hookworm, Ancylostoma caninum
Open accessAbstract
Soil-transmitted nematodes infect over a billion people and place several billion more at risk of infection. Hookworm disease is the most significant of these soil-transmitted nematodes, with over 500 million people infected. Hookworm infection can result in debilitating and sometimes fatal iron-deficiency anemia, which is particularly devastating in children and pregnant women. Currently, hookworms and other soil-transmitted nematodes are controlled by administration of a single dose of a benzimidazole to targeted populations in endemic areas. While effective, people are quickly re-infected, necessitating frequent treatment. Widespread exposure to anthelmintic drugs can place significant selective pressure on parasitic nematodes to generate resistance, which has severely compromised benzimidazole anthelmintics for control of livestock nematodes in many areas of the world. Here we report, to our knowledge, the first naturally occurring multidrug-resistant strain of the canine hookworm Ancylostoma caninum. We reveal that this isolate is resistant to fenbendazole at the clinical dosage of 50 mg/kg for 3 days. Our data shows that this strain harbors a fixed, single base pair mutation at amino acid 167 of the β-tubulin isotype 1 gene, and by using CRISPR/Cas9 we demonstrate that introduction of this mutation into the corresponding amino acid in the orthologous β-tubulin gene of Caenorhabditis elegans confers a similar level of resistance to thiabendazole. We also show that the isolate is resistant to the macrocyclic lactone anthelmintic ivermectin. Understanding the mechanism of anthelmintic resistance is important for rational design of control strategies to maintain the usefulness of current drugs, and to monitor the emergence of resistance. The isolate we describe represents the first multidrug-resistant strain of A. caninum reported, and our data reveal a resistance marker that can emerge naturally in response to heavy anthelminthic treatment.
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“In contrast, data shown in Kitchen et al. [34] indicate that inhibition greater than 80% was not achieved and shapes of dose response curves were not sigmoidal.”
From Multiple drug resistance in the canine hookworm Ancylostoma caninum: an emerging threat? (2019) · cites this paper as [34]
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“The IC50 reported for their resistant isolate was lower than what we measured in our susceptible isolate and the IC50 reported for their susceptible isolate was at pM levels, almost 5000-fold lower than what we measured.”
From Multiple drug resistance in the canine hookworm Ancylostoma caninum: an emerging threat? (2019) · cites this paper as [34]
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In the citing paper
“This yielded resistance ratio of greater than 1000; a level that is greater than what has been reported, even in the most resistant Haemonchus isolates.”
From Multiple drug resistance in the canine hookworm Ancylostoma caninum: an emerging threat? (2019) · cites this paper as [34]
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“a recent publication reported resistance to benzimidazoles and macrocyclic lactones in an isolate of A. caninum obtained from a greyhound dog [34].”
From Multiple drug resistance in the canine hookworm Ancylostoma caninum: an emerging threat? (2019) · cites this paper as [34]
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“Coincident with our studies, a separate recent study reported resistance to benzimidazoles and macrocyclic lactones in A. caninum recovered from a greyhound dog [34].”
From Multiple drug resistance in the canine hookworm Ancylostoma caninum: an emerging threat? (2019) · cites this paper as [34]
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“The poor discrimination for resistance to benzimidazoles was similar to that recently reported for A. caninum [34].”
From Multiple drug resistance in the canine hookworm Ancylostoma caninum: an emerging threat? (2019) · cites this paper as [34]
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“We measured a 5.5 resistance ratio for the Lacy isolate, thus their analyses demonstrated a resistance ratio more than 200 times greater than what we measured.”
From Multiple drug resistance in the canine hookworm Ancylostoma caninum: an emerging threat? (2019) · cites this paper as [34]
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“Furthermore, using CRISPR/Cas 9, Kitchen et al. [34] were successful in replicating this SNP in the homologous ben-1 gene of C. elegans and saw a doubling of the resistance ratio in the EHA, which was similar to the resistance ratio measured in their A. caninum resistant isolate using the LDA [34].”
From Multiple drug resistance in the canine hookworm Ancylostoma caninum: an emerging threat? (2019) · cites this paper as [34]
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“However, Kitchen et al. [34] reported values that are vastly different, both in terms of IC50 level and in magnitude of resistance ratio.”
From Multiple drug resistance in the canine hookworm Ancylostoma caninum: an emerging threat? (2019) · cites this paper as [34]
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“Recently, this same SNP was also reported in a resistant isolate of A. caninum that was originally isolated from a racing greyhound from Florida.”
From Multiple drug resistance in the canine hookworm Ancylostoma caninum: an emerging threat? (2019) · cites this paper as [34]
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Citations
Cites
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Cloning of an avermectin-sensitive glutamate-gated chloride channel from Caenorhabditis elegans
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Flagged first, then by citations
Research works printed but not linked: 1
- Hawdon, 1991, Long-term storage of hookworm infective larvae in buffered saline solution maintains larval responsiveness to host signals, J. Helm. Soc. Wash., 58, 140
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Items 101–105 of 105
Stafford, K., Kollasch, T. M., Duncan, K. T., Horr, S., Goddu, T., Heinz-Loomer, C., Rumschlag, A. J., Ryan, W. G., Sweet, S., & Little, S. E. (2020) · Figshare · doi:10.6084/m9.figshare.12413849
Hooksnip: A Browser Tool for Designing Allele-Specific PCR Primers in Hookworm
Jackson, C. A., Hawdon, J. M., & O’Halloran, D. M. (2026) · Journal of Parasitology · doi:10.1645/25-88
Self-citationDini, M., Chen, R., Redman, E., Leutenegger, C. M., Tereski, J., Loo, S., Savard, C., Castro, P. D. J., Miyashiro, S. I., & Gilleard, J. S. (2026) · International Journal for Parasitology Drugs and Drug Resistance · doi:10.1016/j.ijpddr.2026.100643
McKean, E. L., Jackson, C. A., O’Halloran, D. M., & Hawdon, J. M. (2026) · Journal of Parasitology · doi:10.1645/25-80
Self-citationAnthelmintic Resistance in Companion Animal Parasites
Chelladurai, J. R. J. J., & Brewer, M. T. (2026) · Veterinary Clinics of North America Small Animal Practice · doi:10.1016/j.cvsm.2026.06.002
Metadata
- Authors
- Kitchen, S., Ratnappan, R., Han, S., Leasure, C., Grill, E., Iqbal, Z., Granger, O., O'Halloran, D. M., & Hawdon, J. M.
- Affiliations
- George Washington University (US)
- Corresponding author
- Hawdon, John M.
- Venue
- International Journal for Parasitology
- Publisher
- Elsevier BV
- Published
- 2019-04
- Volume
- 49
- Issue
- 5
- Pages
- 397-406
- ISSN
- 0020-7519 (ISSN-L)
- PMC
- PMC6456372
- OpenAlex
- W2911807104
- Cited by
- 105
- References
- 76
- Citations by year
- 2026: 5 · 2025: 17 · 2024: 19 · 2023: 15 · 2022: 16 · 2021: 11 · 2020: 19 · 2019: 3
- FWCI
- 16.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- International Journal for Parasitology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1R21AI115012)
- Topics
- Life Sciences › Immunology and Microbiology › Parasitology › Helminth infection and control
- Life Sciences › Immunology and Microbiology › Parasitology › Parasites and Host Interactions
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Nematode management and characterization studies
- Keywords
- Ancylostoma caninum, multidrug resistance, anthelmintic resistance, thiabendazole resistance, ivermectin resistance, beta-tubulin mutations, soil-transmitted nematodes, benzimidazole, macrocyclic lactones, CRISPR/Cas9, Caenorhabditis elegans, resistance markers, iron deficiency anemia
- MeSH terms
- Ancylostoma, Animals, Anthelmintics, Base Sequence, Dog Diseases, Dogs, Drug Resistance, Female, Hookworm Infections, Ivermectin, Male, Phylogeny, Thiabendazole, Tubulin, Helminth Proteins
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