Overcoming multidrug-resistance in hookworms

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Project Summary Ancylostoma caninum causes cutaneous larva migrans and eosinophilic enteritis in humans. The reason these human diseases cannot be eliminated is because the parasite persists in the canine reservoir host. Multi-drug resistant isolates of A. caninum are now circulating in the United States. In addition, specific life cycle stages (tissue- dwelling larvae) are tolerant of anthelmintics even when the isolate is considered “drug susceptible.” Our hypothesis is that A. caninum evades drug treatment with permeability glycoproteins (P-glycoproteins) that efflux anthelmintics and prevent them from binding target receptors. In this application we propose to 1) identify the spectrum of anthelmintics enhanced by P-glycoprotein inhibition in A. caninum, 2) record the repertoire of Pgps expressed in response to each drug class, 3) map the precise tissues where Pgps are expressed, 4) characterize the pharmacological profile of Aca-Pgp-11, and 5) empirically determine regions of specific sites of nematode P-glycoprotein that could be exploited. Our results will inform future studies testing the hypothesis that nematode-specific P-glycoprotein inhibitors can be used to restore efficacy of multiple existing anthelmintics and overcome drug resistant Ancylostoma.