P-glycoproteins and other multidrug resistance transporters in the pharmacology of anthelmintics: Prospects for reversing transport-dependent anthelmintic resistance

Abstract

Parasitic helminths cause significant disease in animals and humans. In the absence of alternative treatments, anthelmintics remain the principal agents for their control. Resistance extends to the most important class of anthelmintics, the macrocyclic lactone endectocides (MLs), such as ivermectin, and presents serious problems for the livestock industries and threatens to severely limit current parasite control strategies in humans. Understanding drug resistance is important for optimizing and monitoring control, and reducing further selection for resistance. Multidrug resistance (MDR) ABC transporters have been implicated in ML resistance and contribute to resistance to a number of other anthelmintics. MDR transporters, such as P-glycoproteins, are essential for many cellular processes that require the transport of substrates across cell membranes. Being overexpressed in response to chemotherapy in tumour cells and to ML-based treatment in nematodes, they lead to therapy failure by decreasing drug concentration at the target. Several anthelmintics are inhibitors of these efflux pumps and appropriate combinations can result in higher treatment efficacy against parasites and reversal of resistance. However, this needs to be balanced against possible increased toxicity to the host, or the components of the combination selecting on the same genes involved in the resistance. Increased efficacy could result from modifying anthelmintic pharmacokinetics in the host or by blocking parasite transporters involved in resistance. Combination of anthelmintics can be beneficial for delaying selection for resistance. However, it should be based on knowledge of resistance mechanisms and not simply on mode of action classes, and is best started before resistance has been selected to any member of the combination. Increasing knowledge of the MDR transporters involved in anthelmintic resistance in helminths will play an important role in allowing for the identification of markers to monitor the spread of resistance and to evaluate new tools and management practices aimed at delaying its spread.

Keywords: Anthelmintic resistance; Macrocyclic lactones; Multidrug ABC transporters; P-glycoproteins.

Graphical abstract

Fig. 1

Multidrug transporter-mediated efflux of drug, its contribution to the development of resistance and mechanism of reversion. (A) Constitutive expression of MDR transporters on cell membranes of target organism: basal efflux of drugs (example with macrocyclic lactones). (B) Overexpression of MDR transporters in response to drug pressure: increased efflux of drug and development of resistance. (C) Inhibition of MDR-mediated efflux with MDR reversal agents: enhancement of drug concentration and toxicity into the target cells.

Fig. 2

Putative targets for reversing multidrug transporter-mediated resistance. Different strategies could be considered to increase drug concentration in the target cell in the case of MDR transporter-mediated resistance and to overcome this resistance. (i) Inhibition of MDR transporter-mediated efflux by using MDR inhibitors. (ii) Modulation of MDR transporter gene expression at transcriptional level through an inhibition of transcriptional regulator activity (iia); or at post-transcriptional level through a decrease of the MDR mRNA stability in the cell (iib). (iii) Modulation of lipid composition of the cell membrane harbouring the MDR transporters with surfactants or cholesterol depletion to decrease the basal activity of MDR transporters. (iv) Another side mechanism associated with the presence of MDR substrates is the modulation of oxidative stress with an increase of reactive oxygen species (ROS) production and cell damage resulting in apoptosis induction.