On the mechanism of resistance of parasitic nematodes to anthelmintic drugs (brief review)

The purpose of the research is to analyze the literature devoted to the study of one of the factors in the development of resistance of parasitic nematodes to anthelmintic drugs which has a genetic basis.

The article analyzes the role of genetic mutations identified in populations of parasitic nematodes in vertebrates that do not show sensitivity to benzimidazoles, macrocyclic lactones and acetylcholinergic agonists and antagonists. The literature shows that benzimidazole resistance in parasitic nematodes, by the example of the nematode Haemonchus contortus, is associated with mutations in the β-tubulin encoding isotype 1 gene gru-1, which is a target for benzimidazoles in the body of nematodes. For the nematode resistance to macrocyclic lactones which are glutamate receptor agonists, it was shown by the example of the nematode Caenorhabditis elegans that mutations of three glc-1, avr-14, and avr-15 genes that encode the α-type subunits of glutamate-gated chloride channels of receptors give rise to the development of nematode resistance to macrocyclic lactone ivermectin. Parasitic nematode resistance to cholinergic anthelmintics (levamisole, pyrantel, oxantel), by the example of the nematode Ascaris suum, is associated with mutations in the Asu-UNC-29 and Asu-UNC-38 subunit-encoding genes which form three types of nicotinic acetylcholine nematode receptors, N, L and B. The significance of nematicide resistance as a phenomenon in plant parasitic nematodes has not yet been fully resolved. The phytonematode ecology and biology allow them to survive unfavorable conditions of existence. There are few studies evidencing the probability of detecting resistance in phytoparasitic nematodes to chemical means of protection. Studies are actively conducted to search genetic markers of resistance to various nematicides on the model free-living nematode C. elegans, which will allow us to create new nematicides against both zooparasitic and phytonematodes.

1. Kalinnikova T. B. Soil nematode Caenorhabditis elegans as a model to study parasitic Nematoda. Laboratornyye zhivotnyye dlya nauchnykh issledovaniy = Laboratory Animals for Science. 2024; 1. 61–68. (In Russ). https://doi.org/10.57034/2618723X-2024-01-07

2. Kalinnikova T. B., Gainutdinov M. Kh., Shagidullin R. R. Anthelmintics resistance: the problem and means to overcome it. Veterinarnyy vrach = The Veterinarian. 2018; 5: 36-41. (In Russ)

3. Panova O. A., Arkhipov I. A., Baranova M. V., Khrustalev A. V. The problem of anthelminthic resistance in horse breeding. Rossiyskiy parazitologicheskiy zhurnal = Russian Journal of Parasitology. 2022; 16 (2): 230–242. (In Russ.). https://doi.org/10.31016/1998-8435-2022-16-2-230-242

4. Baiak B. H. B., Lehnen C. R., Rocha R. A. Anthelmintic resistance in cattle: a systematic review and meta-analysis. Livestock Science. 2018; 217: 127–135. https://doi.org/10.1016/j.livsci.2018.09.022

5. Beech R. N., Skuce P., Bartley D. J. et al. Anthelmintic resistance: markers for resistance, or susceptibility? Parasitology. 2011; 138 (2): 160–174. https://doi.org/10.1017/S0031182010001198

6. Berenbaum M. Committee on the future role of pesticides, National Academy of Sciences. The future role of pesticides in U. S. Agriculture. National Academy Press, Washington, D. C., 2000; 48.

7. Burns A. R., Luciani G. M., Musso G. Caenorhabditis elegans is a useful model for anthelmintic discovery. Nature Communications. 2020; 11 (1): 3779. https://doi.org/10.1038/s41467-020-17617-3

8. Chitwood D. J. Nematicides. In Encyclopedia of Agrochemicals; Plimmer J. R., Ed.; John Wiley & Sons: New York, NY, USA, 2003; 1104–1115. https://doi.org/10.1002/047126363X

9. Cully D. F., Vassilatis D. K., Liu K. K. et al. Cloning of an avermectin-sensitive glutamate-gatedchloride channel from Caenorhabditis elegans. Nature.1994; 371 (6499): 707-711. https://doi.org/10.57034/2618723X-2024-01-07

10. Dent J. A., McHardy M. Smith, Vassilatis D. K., Avery L. The genetics of ivermectin resistance in Caenorhabditis elegans. PNAS. 2000; 97 (6): 2674-2679. https://doi.org/10.1073/pnas.97.6.2674

11. Drudge J. H., Szanto J., Wyant Z. N., Elam G. W. Field studies on parasite control of sheep: comparison of thiabendazole, ruelene and phenothiazine. American Journal of Veterinary Research. 1964; 25: 1512–1518.

12. Fissiha W., Kinde M. Z. Anthelmintic resistance and its mechanism: A review. Infection and Drug Resistance. 2021; 14: 5403-5410. https://doi.org/10.2147/IDR.S332378

13. Gilleard J. S., Beech R. N. Markers for anthelmintic resistance. Parasitology. 2007; (8): 1133–1147. https://doi.org/10.1017/S0031182007000066

14. Holden-Dye L. , Walker R. J. Anthelmintic drugs and nematicides: studies in Caenorhabditis elegans. WormBook. 2014; 1-29. https://doi.org/10.1895/wormbook.1.143.2

15. Kaminsky R. et al. A new class of anthelmintics effective against drug-resistant nematodes. Nature. 2008; 452 (7184): 176–180. https://doi.org/10.1038/nature06722

16. Kenealy J. S. Anthelmintic Resistance in Equine Parasites: Mechanisms and Treatment Approaches. University of Kentucky Uknowledge, 2019; 288.

17. Köhler P. The biochemical basis of anthelmintic action and resistance. International Journal for Parasitology. 2001; 31 (4): 336-345. https://doi.org/10.1016/s0020-7519(01)00131-x

18. Kwa M. S., Veenstra J. G., Roos M. H. Molecular characterization of beta-tubulin genes present in benzimidazole-resistant populations of Haemonchus contortus. Molecular and Biochemical Parasitology. 1993; 60 (1): 133-143. https://doi.org/10.1016/0166-6851(93)90036-w

19. Kwok T. C. et al. A small-molecule screen in C. elegans yields a new calcium channel antagonist. Nature. 2006; 441: 91–95.

20. La Grange R., Mandiriza G., van Zyl C. Nematodes, nematicides and resistance management. Compiled by IRAC South Africa, March 2021. https://irac-online.org/documents/nematicides-andresistance-management/?ext=pdf.

21. Lamassiaude N., Courtot E., Corset A. et al. Pharmacological characterization of novel heteromeric GluCl subtypes from Caenorhabditis elegans and parasitic nematodes. British Journal of Pharmacology. 2022; 179 (6): 1264–1279. https://doi.org/10.1111/bph.15703

22. Lin Y., Tsay T. Differences in induced nematicideresistance between free-living and plant-parasitic nematodes. Journal of Nematology. 2007; 39 (1): 85-85.

23. Lubega G. W., Prichard R. K. Specific interaction of benzimidazole anthelmintics with tubulin: highaffinity binding and benzimidazole resistance in Haemonchus contortus. Molecular and Biochemical Parasitology. 1990; 15. 38 (2): 221-232. https://doi.org/10.1016/0166-6851(90)90025-hJan

24. Martin R. J. Modes of action of anthhelmintic drugs. Veterinary Journal. 1997; 154 (1): 11-34. https://doi.org/10.1016/s1090-0233(05)80005-x

25. Martin R. J., Verma S., Levandoski M. et al. Drug resistance and neurotransmitter receptors of nematodes: recent studies on the mode of action of levamisole. Parasitology. 2005; S71–S84. https://doi.org/10.1017/S0031182005008668

26. Mickiewicz M., Czopowicz M., Moroz A. et al. Prevalence of anthelmintic resistance of gastrointestinal nematodes in Polish goat herds assessed by the larval development test. BMC Veterinary Research. 2021; 17 (19): 1–12. https://doi.org/10.1186/s12917-020-02721-9

27. Moens M., Hendrickx G. Effect of long term aldicarb applications on the development of field populations of some endoparasitic nematodes. Fundamental and Applied Nematology. 1998; 21: 199–204.

28. Molento M. B. Parasite control in the age of drug resistance and changing agricultural practices. Veterinary Parasitology. 2009; 163 (3): 229-234.

29. Peña-Espinoza M. Drug resistance in parasitic helminths of veterinary importance in Chile: status review and research needs. Austral Journal of Veterinary Sciences. 2018; 50: 65–76. https://doi.org/10.4067/S0719-81322018000200065

30. Potârniche A. V., Mickiewicz M., Olah D. et al. First report of anthelmintic resistance in gastrointestinal nematodes in goats in Romania. Animals. 2021; 11: 2761. https://doi.org/10.3390/ani1110276

31. Prichard R. K. Genetic variability following selection of Haemonchus сontortus with anthelmintics. Trends in parasitology. 2001; 17 (9): 445-453.

32. Prichard R. K., Lespine A. Genetics and mechanisms resistance in Nematodes. In M. B. Kennedy, W. Harnett. Parasitic nematodes: molecular biology, biochemistry and immunology. 2013; https://doi.org/10.1079/9781845937591.0156

33. Qian H., Martin R. J., Robertson A. P. Pharmacology of N-, L-, and B-subtypes of nematode nAChR resolved at the single-channel level in Ascaris suum. FASEB Journal. 2006; 20 (14): 2606-2608. https://doi.org/10.1096/fj.06-6264fje

34. Rozhkova E. K., Malyutina T. A., Shishov B. A. harmacological characteristics of cholinoreception in somatic muscules of the nematode Ascaris suum. General Pharmacology. 1980; 11: 141-146.

35. Wolstenholme A. J. Ion channels and receptor as targets for the control of parasitic nematodes. International Journal for Parasitology – Drugs and Drug Resistance. 2011; 1 (1): 2–13. https://doi.org/10.1016/j.ijpddr.2011.09.003

36. Wolstenholme A. J., Rogers A. T. Glutamategated chloride channels and the mode of action of the avermectin/milbemycin anthelmintics. Parasitology. 2005; 131: S85–S95. https://doi.org/10.1017/S0031182005008218

37. Ymashlta T. T., Viglierchio D. R. In vitro testing for nonfumiganr nematicide resistance in Xiphinema index. Revue de Nématologie. 1987; 10: 75-79.