Relative potency of macrocyclic lactones in in vitro assays with larvae of susceptible and drug-resistant Australian isolates of Haemonchus contortus and H. placei

Kotze, Andrew C.; Ruffell, Angela P.; Knox, Malcolm; Kelly, Gareth Andrew

doi:10.1016/j.vetpar.2014.04.005

Cited by 21 publications

(13 citation statements)

References 20 publications

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“…These results are in full agreement with data from previous in vivo studies, which showed that MOX efficacy is maintained at higher levels than is IVM efficacy as ML resistance develops, as well as in vitro studies on drug-resistant parasitic nematodes, where MOX was more potent than IVM, while EPR was the least potent drug, displaying the highest resistance ratio compared to IVM and MOX (35,(43)(44)(45)(46)(47)(48)(49)(50)(51). These similarities with the ML-selected C. elegans strains clearly show that the model of drug selection pressure in C. elegans can be relevant to studies of the adaptation of parasitic nematodes to ML treatment in the field.…”

Section: Discussionsupporting

confidence: 91%

Acquired Tolerance to Ivermectin and Moxidectin after Drug Selection Pressure in the Nematode Caenorhabditis elegans

Ménez

Alberich

Kansoh

et al. 2016

Antimicrob Agents Chemother

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cIvermectin and moxidectin are the most widely administered anthelmintic macrocyclic lactones (MLs) to treat human and animal nematode infections. Their widespread and frequent use has led to a high level of resistance to these drugs. Although they have the same mode of action, differences in terms of selection for drug resistance have been reported. Our objective was to study and compare changes occurring upon ivermectin or moxidectin selection in the model nematode Caenorhabditis elegans. C. elegans worms were submitted to stepwise exposure to increasing doses of moxidectin. The sensitivity of moxidectin-selected worms to MLs was determined in a larval development assay and compared with those of wild-type and ivermectin-selected strains. Selection with either ivermectin or moxidectin led to acquired tolerance to ivermectin, moxidectin, and eprinomectin. Importantly, moxidectin was the most potent ML in both ivermectin-and moxidectin-selected strains. Interestingly, this order of potency was also observed in a resistant Haemonchus contortus isolate. In addition, ivermectin-and moxidectin-selected strains displayed constitutive overexpression of several genes involved in xenobiotic metabolism and transport. Moreover, verapamil potentiated sensitivity to ivermectin and moxidectin, demonstrating that ABC transporters play a role in ML sensitivity in ML-selected C. elegans strains. Finally, both ivermectin-and moxidectin-selected strains displayed a dye-filling-defective phenotype. Overall, this work demonstrated that selection with ivermectin or moxidectin led to cross-resistance to several MLs in nematodes and that the induction of detoxification systems and defects in the integrity of amphidial neurons are two mechanisms that appear to affect the responsiveness of worms to both ivermectin and moxidectin.T he broad-spectrum anthelmintic macrocyclic lactones (MLs) are most commonly used in veterinary medicine to treat diseases caused by gastrointestinal nematodes and external parasites in livestock (1, 2). Ivermectin (IVM) was the first ML approved for use in animals and remains today the sole ML registered for use in humans, mainly to treat onchocerciasis through mass chemotherapy. Another ML, moxidectin (MOX), was subsequently commercialized for the veterinary market and is currently being evaluated for possible use against human onchocerciasis (3). Inevitably, the intensive use of these compounds has led to the emergence of resistance in small ruminant, cattle, and some human nematode parasites (4-7). Discovering the mechanisms by which resistance to MLs occurs remains an important challenge today.There is consistent evidence that ATP-binding-cassette (ABC) transporters such as P-glycoproteins (Pgps) play an important role in multidrug resistance (MDR) in many organisms, including several nematode species. Gene expression levels of ABC transporters or allele frequencies were modified after ML selection (8-13), and they are involved in the tolerance of Caenorhabditis elegans (9, 14-16) and parasitic nematodes s...

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Section: Discussionsupporting

confidence: 91%

Acquired Tolerance to Ivermectin and Moxidectin after Drug Selection Pressure in the Nematode Caenorhabditis elegans

Ménez

Alberich

Kansoh

et al. 2016

Antimicrob Agents Chemother

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“…For example, while Wallangra adults are unaffected by a full dose of moxidectin in vivo, the present study found that this isolate showed a resistance ratio in the larval development assay with ivermectin of only 17, while an earlier study reported a resistance ratio of only 4-fold toward moxidectin itself (Kotze et al, 2014b). The egg hatch assay resistance ratios reported for H. contortus isolates showing resistance to benzimidazoles generally range up to about 20-fold (for example, von Samson-Himmelstjerna et al, 2009).…”

Section: Resultscontrasting

confidence: 54%

“…ivermectin of approximately 13-20 fold in larval development assays (Kotze et al, 2014b;Raza et al, 2015), compared to approximately 3-fold in a migration assay (Raza et al, 2015), and zero (no resistance detected) in a motility assay (Smout et al, 2010).…”

Section: Introductionmentioning

confidence: 97%

The role of drug efflux systems in anthelmintic resistance in parasitic nematodes

Raza¹

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“…However, it is well known that anthelmintic drugs are not all equally able to prevent embryonation and hatching of nematode eggs, as this is a prerogative especially of benzimidazoles, while other anthelmintic drugs, as for example macrocyclic lactones, have no such ability [ 29 , 30 , 31 , 36 ]. This is the main reason why in studies evaluating the anthelmintic resistance of ruminant GIS strains, the EHT is used mainly for the detection of resistance to benzimidazoles [ 29 , 30 , 31 , 36 ]. Therefore, a reduced or absent efficacy of a molecule in this test should not necessarily be interpreted as indicative of low or absent anthelmintic properties.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Anthelmintic Activity of Four Plant-Derived Compounds against Sheep Gastrointestinal Nematodes

Giovanelli

Mattellini

Fichi

et al. 2018

Veterinary Sciences

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By using the egg hatch test (EHT), the larval development test (LDT) and the larval mortality/paralysis test (LMT), the in vitro anthelmintic activity on sheep gastrointestinal strongyles (GIS) of four plant-derived pure compounds, mangiferin (at 0.25%, 0.125% and 0.0625%), rutin (at 1%, 0.75%, 0.5%), quercetin (at 1%), and β-sitosterol (at 1%, 0.75%, 0.5%), was investigated. For comparison, untreated and treated (0.1% thiabendazole, 0.1% TBZ) controls were used. Six repetitions were made throughout the experiment. Data were statistically elaborated using the χ2 test. The concentration able to inhibit the development of the 50% of L1s to L3s and causing the mortality of the 50% of L3s (EC50) was also calculated. L3s recovered from untreated Petri dishes were identified at the genus level. In EHT, all tested compounds at all concentrations significantly (p < 0.01) inhibited the hatch of the eggs when compared to the untreated controls, but none of them was as effective as 0.1% TBZ. In LDT, rutin (at 1%, 0.75% and 0.5%), mangiferin (at 0.25% and 0.125%), β-sitosterol (at 1%) and 0.1% TBZ completely prevented the larval development from L1 to L3 in respect to the untreated controls (p < 0.01). In LMT, all tested compounds significantly (p < 0.01) increased the death of L3s compared to the untreated controls, except for β-sitosterol at 0.5%. However, only rutin at all concentrations and 0.25% and 0.125% mangiferin were as effective as 0.1% TBZ. Haemonchus, Trichostrongylus, Chabertia and Teladorsagia/Ostertagia GIS genera, were identified.

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Relative potency of macrocyclic lactones in in vitro assays with larvae of susceptible and drug-resistant Australian isolates of Haemonchus contortus and H. placei

Cited by 21 publications

References 20 publications

Acquired Tolerance to Ivermectin and Moxidectin after Drug Selection Pressure in the Nematode Caenorhabditis elegans

Acquired Tolerance to Ivermectin and Moxidectin after Drug Selection Pressure in the Nematode Caenorhabditis elegans

The role of drug efflux systems in anthelmintic resistance in parasitic nematodes

In Vitro Anthelmintic Activity of Four Plant-Derived Compounds against Sheep Gastrointestinal Nematodes

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