Sub-lethal doses of albendazole induce drug metabolizing enzymes and increase albendazole deactivation in Haemonchus contortus adults

Kellerová, Pavlína; Stuchlíková, Lucie Raisová; Matoušková, Petra; Štěrbová, Karolína; Lamka, J.; Navrátilová, Martina; Vokřál, Ivan; Szotáková, Barbora; Skálová, Lenka

doi:10.1186/s13567-020-00820-x

Cited by 22 publications

(21 citation statements)

References 44 publications

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“…In C. elegans , it was shown that the cytochrome P450 Cyp-35d1 is able to oxidise thiabendazole, which is then conjugated to glucose and that downregulation of cyp-35d1 makes worms more susceptible to the effects of thiabendazole on egg laying in both a wild-type and a BZ-resistant, ben-1-deficient genetic background. Both C. elegans and H. contortus have been shown to metabolise several BZs (albendazole, mebendazole, thiabendazole, oxfendazole, fenbendazole and flubendazole) to hexose conjugates [ 70 , 71 , 72 ]. Data about metabolisation of anthelmintic drugs by ascarid nematodes have not been published, but changes in metabolic pathways, such as increased activity, obviously represent another option how anthelmintic resistance might be established in ascarids.…”

Section: Discussionmentioning

confidence: 99%

Absence of Polymorphisms in Codons 167, 198 and 200 of All Seven β-Tubulin Isotypes of Benzimidazole Susceptible and Resistant Parascaris spp. Specimens from Australia

et al. 2022

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Benzimidazoles resistance is widespread in strongyle parasitic nematodes and associated with polym orphisms in the codons 167, 198 and 200 of isotype 1 β-tubulin (tbb-1). In ascarids, benzimidazole (BZ) resistance has rarely been reported and in none of these cases were any of these polymorphisms detected. Here, available genome and transcriptome data from WormBase ParaSite were used to compare the complete β-tubulin reservoirs of Parascaris univalens, Ascaris suum and Ascaris lumbricoides. Adult Parascaris spp. specimens collected in Australia from horses after BZ treatment (susceptible, n = 13) or surviving BZ treatment and collected after ivermectin treatment (resistant, n = 10) were genotyped regarding codons 167, 198 and 200 using Sanger sequencing. Phylogenetic analyses clearly showed that there are no one-to-one ascarid orthologs of strongyle tbb-1 genes. In the reference genomes, as well as phenotypically susceptible and resistant Parascaris spp. from Australia, six out of seven β-tubulin genes showed a BZ-susceptible genotype (F167, E198, F200). The only exception were the testis-specific β-tubulin D genes from all three ascarid species that encode tyrosine at codon 200. This was observed independently of the BZ-susceptibility phenotype of Parascaris spp. These data suggest that different mechanisms lead to BZ resistance in ascarid and strongyle nematodes.

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Section: Discussionmentioning

confidence: 99%

Absence of Polymorphisms in Codons 167, 198 and 200 of All Seven β-Tubulin Isotypes of Benzimidazole Susceptible and Resistant Parascaris spp. Specimens from Australia

et al. 2022

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“…In addition, it has been suggested that mutations in the isotype 1 gene are not solely responsible, but that BZ resistance may be multi-genic. For example, SNPs in the H. contortus β-tubulin isotype 2 gene have been correlated to BZ resistance in field strains ( Kwa et al, 1993a , 1993b ) and BZ drugs have also been shown to influence the expression of drug metabolizing enzymes and drug efflux pumps ( Beugnet et al, 1997 ; Laing et al, 2010 ; Jones et al, 2013 ; Kellerova et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Exploring the β-tubulin gene family in a benzimidazole-resistant Parascaris univalens population

Martin

Halvarsson

Delhomme

et al. 2021

International Journal for Parasitology: Drugs and Drug Resistan

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Benzimidazole (BZ) drugs are frequently used to treat infections with the equine ascarid Parascaris univalens due to increasing resistance to macrocyclic lactones and pyrantel. Benzimidazole resistance is rare in ascarids in contrast to strongyle parasites where this resistance is widespread. In strongyles, single nucleotide polymorphisms (SNPs) at codons 167, 198 and 200 in a β-tubulin gene have been correlated to BZ resistance, but little is known about the β-tubulin genes and their possible involvement in BZ resistance in P. univalens and other ascarids. Previously two β-tubulin genes have been identified in P. univalens . In this study, we present five additional β-tubulin genes as well as the phylogenetic relationship of all seven genes to β-tubulins of other clade III and V nematodes. In addition, the efficacy of fenbendazole for treatment of P. univalens on a Swedish stud farm was studied in 2019 and 2020 using faecal egg count reduction test. Reductions varied from 73% to 88%, indicating the presence of a resistant P. univalens population on the farm. The emergence of BZ resistance emphasizes the need for development of molecular markers for rapid and more sensitive detection of resistant populations. We therefore investigated whether possible SNPs at positions 167, 198 or 200 in any of the β-tubulin genes could be used to distinguish between resistant and susceptible P. univalens populations. Amplicon sequencing covering the mutation sites 167, 198 and 200 in all seven β-tubulin genes revealed an absence of SNPs in both resistant and susceptible populations, suggesting that the mechanism behind BZ resistance in ascarids is different from that in strongyle nematodes and the search for a molecular marker for BZ resistance in P. univalens needs to continue.

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“…Therefore, some focus on the resistance mechanism turned to XMEs. In H. contortus , researchers have reported a potential role of XMEs in resistance to anthelmintics such as albendazole, which was oxidized in adult worms [ 42 ]. Another study showed that silencing the CYP gene (HCON_00143950), which belongs to a class of XME genes, significantly increased the sensitivity of H. contortus larvae to IVM [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Comparative analysis on transcriptomics of ivermectin resistant and susceptible strains of Haemonchus contortus

Tuersong

Zhou

et al. 2022

Parasites Vectors

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Background Ivermectin (IVM) is one of the most important and widely used anthelmintics in veterinary medicine. However, its efficacy is increasingly compromised by widespread resistance, and the exact mechanism of IVM resistance remains unclear for most parasitic nematodes, including Haemonchus contortus, a blood-sucking parasitic nematode of small ruminants. Methods In this study, an H. contortus IVM-resistant strain from Zhaosu, Xinjiang, China, was isolated and assessed by the control test, faecal egg count reduction test (FECRT) and the larval development assay (LDA). Subsequently, comparative analyses on the transcriptomics of IVM-susceptible and IVM-resistant adult worms of this parasite were carried out using RNA sequencing (RNA-seq) and bioinformatics. Results In total, 543 (416 known, 127 novel) and 359 (309 known, 50 novel) differentially expressed genes (DEGs) were identified in male and female adult worms of the resistant strain compared with those of the susceptible strain, respectively. In addition to several previously known candidate genes which were supposed to be associated with IVM resistance and whose functions were involved in receptor activity, transport, and detoxification, we found some new potential target genes, including those related to lipid metabolism, structural constituent of cuticle, and important pathways such as antigen processing and presentation, lysosome, autophagy, apoptosis, and NOD1-like receptor signalling pathways. Finally, the results of quantitative real-time polymerase chain reaction confirmed that the transcriptional profiles of selected DEGs (male: 8 genes, female: 10 genes) were consistent with those obtained by the RNA-seq. Conclusions Our results indicate that IVM has multiple effects, including both neuromuscular and non-neuromuscular targets, and provide valuable information for further studies on the IVM resistance mechanism in H. contortus. Graphical Abstract

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Sub-lethal doses of albendazole induce drug metabolizing enzymes and increase albendazole deactivation in Haemonchus contortus adults

Cited by 22 publications

References 44 publications

Absence of Polymorphisms in Codons 167, 198 and 200 of All Seven β-Tubulin Isotypes of Benzimidazole Susceptible and Resistant Parascaris spp. Specimens from Australia

Absence of Polymorphisms in Codons 167, 198 and 200 of All Seven β-Tubulin Isotypes of Benzimidazole Susceptible and Resistant Parascaris spp. Specimens from Australia

Exploring the β-tubulin gene family in a benzimidazole-resistant Parascaris univalens population

Comparative analysis on transcriptomics of ivermectin resistant and susceptible strains of Haemonchus contortus

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