Characterization of Haemonchus contortus P-glycoprotein-16 and its interaction with the macrocyclic lactone anthelmintics

Godoy, Pablo; Che, Hua; Beech, Robin N.; Prichard, Roger K.

doi:10.1016/j.molbiopara.2015.12.001

Cited by 29 publications

(23 citation statements)

References 51 publications

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“…The cross-resistance phenotype observed in ML-selected strains is certainly based, at least partly, on the overexpression of genes encoding multidrug ABC transporters. Given that the different MLs are structurally related and that they all interact with Pgps of parasitic nematodes (62)(63)(64)(65), it is expected that the overexpression of Pgps in worms will lead to cross-resistance to IVM, MOX, EPR, and eventually other MLs and drugs that are Pgp substrates. Interestingly, MOX interacts weakly with nematode Pgps (62)(63)(64)(65)(66), and this is in agreement with its higher level of toxicity in ML-resistant strains.…”

Section: Discussionmentioning

confidence: 99%

“…Given that the different MLs are structurally related and that they all interact with Pgps of parasitic nematodes (62)(63)(64)(65), it is expected that the overexpression of Pgps in worms will lead to cross-resistance to IVM, MOX, EPR, and eventually other MLs and drugs that are Pgp substrates. Interestingly, MOX interacts weakly with nematode Pgps (62)(63)(64)(65)(66), and this is in agreement with its higher level of toxicity in ML-resistant strains. Moreover, the cross-resistance phenotype between ML compounds in parasitic nematodes was associated with the overexpression of several Pgps (10,13,43,44).…”

Section: Discussionmentioning

confidence: 99%

“…Third, IVM and MOX differentially interact with Pgps and other multidrug resistance (MDR) transporters. Indeed, it was clearly demonstrated that the interaction of MOX with mammalian Pgp (68), but also with H. contortus Pgp-2, Pgp-9, and Pgp-16 (62)(63)(64); Cylicocylus elongatus Pgp-9 (65); and Dirofilaria immitis Pgp-11 (66), is much weaker than that of IVM. Moreover, it was suggested that the MRPs may play less of a role in protecting C. elegans from MOX toxicity than they do in protecting the nematode from IVM toxicity (22).…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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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“…Also, induction of expression of some Pgp genes after selection under IVM pressure is associated with IVM resistance in C. elegans and in several parasitic nematodes, which can be partly reversed by using mammalian Pgp inhibitors (James and Davey, 2009, Lespine et al., 2012, Menez et al., 2016). In addition, ML were shown to inhibit parasitic nematode Pgp-mediated drug transport in heterologous recombinant systems overexpressing Hco-Pgp-2, Hco-Pgp-9.1, Hco-Pgp-16, Cylicocylus elongatus ( Ceg )-Pgp-9 or Dirofilaria immitis ( Dim) -Pgp-11 (Godoy et al., 2015a, Godoy et al., 2015b, Godoy et al., 2016, Kaschny et al., 2015, Mani et al., 2016). Nevertheless, all these data give only indirect evidence that ML can be substrates of nematode Pgps.…”

Section: Introductionmentioning

confidence: 99%

In silico analysis of the binding of anthelmintics to Caenorhabditis elegans P-glycoprotein 1

David

Orlowski

Prichard

et al. 2016

International Journal for Parasitology: Drugs and Drug Resistan

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Macrocyclic lactones (ML) are important anthelmintics used in animals and humans against parasite nematodes, but their therapeutic success is compromised by the spread of ML resistance. Some ABC transporters, such as p-glycoproteins (Pgps), are selected and overexpressed in ML-resistant nematodes, supporting a role for some drug efflux proteins in ML resistance. However, the role of such proteins in ML transport remains to be clarified at the molecular level. Recently, Caenorhabditis elegans Pgp-1 (Cel-Pgp-1) has been crystallized, and its drug-modulated ATPase function characterized in vitro revealed Cel-Pgp-1 as a multidrug transporter. Using this crystal structure, we have developed an in silico drug docking model in order to study the binding of ML and other anthelmintic drugs to Cel-Pgp-1. All tested ML bound with high affinity in a unique site, within the inner chamber of the protein, supporting that ML may be transported by Cel-Pgp-1. Interestingly, interacting residues delineate a ML specific fingerprint involving H-bonds, including T1028. In particular, benzofurane and spiroketal moieties bound to specific sub-sites. When compared with the aglycone ML, such as moxidectin and ivermectin aglycone, avermectin anthelmintics have significant higher affinity for Cel-Pgp-1, likely due to the sugar substituent(s) that bind to a specific area involving H-bonds at Y771. Triclabendazole, closantel and emodepside bound with good affinities to different sub-sites in the inner chamber, partially overlapping with the ML binding site, suggesting that they could compete for Cel-Pgp-1-mediated ML transport. In conclusion, this work provides novel information on the role of nematode Pgps in transporting anthelmintics, and a valuable tool to predict drug-drug interactions and to rationally design new competitive inhibitors of clinically-relevant nematode Pgps, to improve anthelmintic therapeutics.

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“…However, it was recently described that IVM markedly inhibited rhodamine-123 (R-123; a fluorescent substrate) transport through pgp-2, pgp-9.1 and pgp-16 from adult worms of H. contortus expressed in mammalian cells (Godoy et al, 2015a;Godoy et al, 2015b;Godoy et al, 2016), whereas moxidectin caused less inhibition of R-123 efflux as compared to IVM. The authors concluded that IVM is a better substrate of nematode P-gps than moxidectin and this may help to explain the slower rate of development of resistance in H. contortus to moxidectin compared with the avermectins.…”

Section: Abc Transporters and Drug Resistance In Nematodesmentioning

confidence: 99%

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

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Characterization of Haemonchus contortus P-glycoprotein-16 and its interaction with the macrocyclic lactone anthelmintics

Cited by 29 publications

References 51 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

In silico analysis of the binding of anthelmintics to Caenorhabditis elegans P-glycoprotein 1

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

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