Effects of third generation P-glycoprotein inhibitors on the sensitivity of drug-resistant and -susceptible isolates of Haemonchus contortus to anthelmintics in vitro

Raza, Ali, Kopp, Steven R., Jabbar, Abdul and Kotze, Andrew C. (2015) Effects of third generation P-glycoprotein inhibitors on the sensitivity of drug-resistant and -susceptible isolates of Haemonchus contortus to anthelmintics in vitro. Veterinary Parasitology, 211 1-2: 80-88. doi:10.1016/j.vetpar.2015.04.025


Author Raza, Ali
Kopp, Steven R.
Jabbar, Abdul
Kotze, Andrew C.
Title Effects of third generation P-glycoprotein inhibitors on the sensitivity of drug-resistant and -susceptible isolates of Haemonchus contortus to anthelmintics in vitro
Formatted title
Effects of third generation P-glycoprotein inhibitors on the sensitivity of drug-resistant and -susceptible isolates of Haemonchus contortus to anthelmintics in vitro
Journal name Veterinary Parasitology   Check publisher's open access policy
ISSN 1873-2550
0304-4017
Publication date 2015-06-30
Year available 2015
Sub-type Article (original research)
DOI 10.1016/j.vetpar.2015.04.025
Volume 211
Issue 1-2
Start page 80
End page 88
Total pages 9
Place of publication Amsterdam, Netherlands
Publisher Elsevier
Language eng
Formatted 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.
Keyword P-glycoprotein
Inhibitor
Anthelmintic
Resistance
In vitro
Haemonchus contortus
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Veterinary Science Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 9 times in Thomson Reuters Web of Science Article | Citations
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