Interfering with ABC-Transporters as a means to Potentiate the Efficacy of Flukicides

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Poster

Interfering with ABC-Transporters as a means to Potentiate the Efficacy of Flukicides

Authors

N Clarke ³; E McCammick³; B Crooks²; E Robb³; P McVeigh³; L Atkinson³; A Mousley³; J Hodgkinson¹; N J Marks³; A G Maule³;
¹ Institute of Infection and Global Health, University of Liverpool, UK; ² Queen’s University Belfast, UK; ³ Queen's University Belfast, UK

Discussion

Genus Fasciola contains the liver fluke parasites, the causative agents of fascioliasis/fasciolosis, a disease of socioeconomic importance through its impact upon global agriculture and as a neglected tropical disease of humans. Treatment relies upon a small arsenal of flukicides, where triclabendazole (TCBZ) exhibits unique efficacy in treating both acute and chronic infections. With increasing reports of TCBZ resistance both in animals and humans comes an increasing necessity for the exploration of novel drug targets, or novel ways to potentiate the efficacy of current flukicides, e.g. limiting their metabolism and or efflux within the parasite. Utilising our in vitro culture platform, TCBZ and its metabolites (triclabendazole sulphoxide (TCBZSO) and triclabendazole sulphone (TCBZSO2)) are demonstrated as being active against juvenile Fasciola hepatica. Interestingly, TCBZ-resistant isolates exhibit increased tolerance to TCBZSO, the hypothesised active form of the compound. Co-incubation of TCBZ and its metabolites with the ABC-transporter inhibitor verapamil potentiates drug efficacy against F. hepatica, as well as the effectiveness of TCBZSO against a TCBZ-resistant isolate. Probing the available genomic data for F. hepatica revealed 23 putative ABC transporter sequences in the Liverpool genome, whereby orthologues of well-known drug resistance-associated proteins including p-glycoprotein 1, multidrug resistance associated protein (Fhmrp1) and breast cancer resistance protein were found. These transcripts were found to be highly amenable to RNAi-based knockdown, with a reduction in Fhmrp-1 potentiating the efficacy of TCBZSO against a TCBZ-R isolate. These data highlight the drug target candidature of ABC transporters as a way to preserve the efficacy of currently used flukicides.

We acknowledge funding provided by the Biotechnology and Biological Sciences Research Council and Merial Ltd. (BB/K009583/1), the National Centre for the 3Rs (NC/N001486/1) and the Department for the Economy of Northern Ireland.