ABC transport proteins and drug resistance in nematodes

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Widespread resistance to chemotherapeutic agents is one of the biggest challenges facing human health and the agricultural industry, with resistance to all current anthelmintics now recorded. Understanding the development of drug resistance in parasitic nematodes is critical to prolonging the efficacy of current anthelmintics, developing markers for monitoring drug resistance and is beneficial in the design of new chemotherapeutic agents or targets. Multidrug resistance (MDR) is mediated by ATP-binding cassette (ABC) transport proteins including the multidrug resistance-associated proteins (MRPs) and P-glycoproteins, which confer resistance to structurally and functionally different drugs. This work characterizes the role of these proteins in drug resistance in nematodes. Using the model nematode Caenorhabditis elegans, ivermectin resistant sublines were developed through step-wise exposure to increasing concentrations of ivermectin commencing with a non-toxic concentration of 1 ng/ml. Resistant strains displayed a MDR phenotype with cross-resistance not only to the related drug moxidectin, but also to other unrelated anthelmintics, levamisole, pyrantel and thiabendazole but not to albendazole. Resistance was stable after 3 months without tivermectin treatment. Resistance to low levels of ivermectin (≤6 ng/ml) was associated with increased expression of mrp-1, mrp-6 and pgp-1 and decreased glutathione, while higher level resistance (10ng/ml) was primarily associated with the increased expression of P-glycoproteins. This resistance to ivermectin was reversible by the co-administration of MRP, P-glycoprotein and glutathione synthesis inhibitors confirming the involvement of these proteins in resistance. To show the relevance of this model, homologues of MRPs were identified in the gastrointestinal parasitic nematode of ruminants Haemonchus contortus. Increased expression of several MRPs identified in H. contortus was found in ivermectin resistant isolates, supporting the relevance of the C. elegans model. The interaction of ivermectin with human P-glycoprotein and MRP-1 was also examined. lvermectin clearly inhibits the transport of P-glycoprotein substrates and can reverse resistance to both daunorubicin and taxol in resistant cells . An interaction with mammalian MRP-1 is less clear, with a 10-fold lower affinity. Therefore ivermectin and modulators of Pglycoprotein have the potential to interfere with the biodisposition and bioavailability of anthelmintics within parasitic hosts as well as parasites. Overall, this work demonstrated that low doses of ivermectin can induce resistance in nematodes through the increased expression of multidrug resistance transport proteins, adding further complexity of the development of drug resistance, and demonstrating the multi-factorial nature of MDR.
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