title: Effects of third generation P-glycoprotein inhibitors on the sensitivity of drug-resistant and -susceptible isolates of Haemonchus contortus to anthelmintics in vitro.
abstract: P-glycoproteins (P-gps) play an important role in the sensitivity of nematodes to anthelmintic drugs. They have been implicated in a number of anthelmintic resistances, particularly for macrocyclic lactone drugs. Hence, inhibition of nematode P-gps has been suggested as a means of reversing some types of anthelmintic resistance. The present study aimed to investigate the ability of the most-recently developed group of P-gp inhibitors (the so-called 'third generation' of inhibitors) including tariquidar, zosuquidar and elacridar, to increase the sensitivity of Haemonchus contortus larvae to various anthelmintics (ivermectin, levamisole and thiabendazole) in vitro. We compared these compounds to some older P-gp inhibitors (e.g. verapamil and valspodar). Larval migration and development assays were used to measure the sensitivity of larvae to anthelmintics alone, or in combination with P-gp inhibitors. Significant increases in sensitivity to ivermectin were observed with zosuquidar and tariquidar in larval migration assays (synergism ratios up to 6-fold). Several of the inhibitors increased the sensitivity of both the drug-resistant and -susceptible isolates (e.g. tariquidar with ivermectin in migration assays, zosuquidar with ivermectin in larval development assays), while others had significant effects on the resistant isolate only (e.g. zosuquidar with ivermectin in migration assays, verapamil with ivermectin in development assays). This suggests that some of the inhibitors interact with P-gps representing intrinsic pathways present across nematode populations with quite different drug sensitivities, while other inhibitors interact with P-gps of significance only to resistant nematodes, and hence most likely representing an acquired resistance mechanism. The study highlights the potential of the third generation of P-gp inhibitors for increasing the sensitivity of nematodes to anthelmintics.
authors.affiliation: CSIRO Agriculture Flagship, Queensland Bioscience Precinct, University of Queensland, Brisbane, Australia; School of Veterinary Science, University of Queensland, Gatton, Australia.
authors.forename: Ali
authors.initials: A
authors.lastname: Raza
authors.affiliation: School of Veterinary Science, University of Queensland, Gatton, Australia.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Kopp
authors.affiliation: School of Veterinary Science, University of Melbourne, Werribee, Victoria, Australia.
authors.forename: Abdul
authors.initials: A
authors.lastname: Jabbar
authors.affiliation: CSIRO Agriculture Flagship, Queensland Bioscience Precinct, University of Queensland, Brisbane, Australia. Electronic address: andrew.kotze@csiro.au.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Kotze
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D004351:Drug Resistance; D006189:Haemonchus / Q000187:drug effects* / Q000254:growth & development; D007559:Ivermectin / Q000494:pharmacology; D007783:Lactones / Q000494:pharmacology; D007814:Larva / Q000187:drug effects / Q000254:growth & development; D007978:Levamisole / Q000494:pharmacology; D013827:Thiabendazole / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000871:Anthelmintics; D007783:Lactones; D007978:Levamisole; D007559:Ivermectin; D014700:Verapamil; D013827:Thiabendazole
keywords: Anthelmintic; Haemonchus contortus; In vitro; Inhibitor; P-glycoprotein; Resistance