Macrocyclic Lactones Differ in Interaction with Recombinant P-Glycoprotein 9 of the Parasitic Nematode and Ketoconazole in a Yeast Growth Assay

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Macrocyclic lactones (MLs) are widely used drugs against parasitic nematodes, but drug resistance is rapidly increasing in prevalence and spatial distribution in parasites of ruminants and horses, and is suspected in human nematodes after mass drug applications. Changes in expression levels or the amino acid sequences of P-glycoprotein (Pgp) transporters have frequently been implicated in ML resistance, but direct evidence for transport of MLs by nematode Pgps is still missing. Here, cloning of pgp-9 of the equine parasite Cylicocyclus elongatus and its functional recombinant expression in a Saccharomyces cerevisiae yeast strain deficient in seven endogenous ABC transporters is described. Expression decreased susceptibility to several fungicidal mammalian Pgp substrates including e.g. actinomycin D and ketoconazole, but had no influence on susceptibility to the benzimidazole thiabendazole, which is active against both, yeasts and nematodes. Addition of some MLs strongly increased ketoconazole susceptibility in yeasts expressing C. elongatus Pgp-9, while other MLs had no effect. These interactions are a strong hint that some MLs act as substrates or at least as inhibitors of Pgp-9 mediated drug transport.

Vyšlo v časopise: Macrocyclic Lactones Differ in Interaction with Recombinant P-Glycoprotein 9 of the Parasitic Nematode and Ketoconazole in a Yeast Growth Assay. PLoS Pathog 11(4): e32767. doi:10.1371/journal.ppat.1004781
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004781

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