WP 6 - Control of P-glycoprotein in both host and parasite for an improvement of anthelmintic treatment

Objectives

A key problem in the control of gastro-intestinal parasites of ruminants is the maintenance of anthelmintic efficacy in the face of increasing resistance. One way of combating this is to ensure the maximum effect of the drug by inhibiting the mechanisms responsible for detoxification. Among these, we previously showed that the increased activity of cellular «pumps», the P-glycoprotein (Pgp), that eliminate drugs in both host and parasite cells, is responsible for the major part of drug resistance or treatment failure. Most anthelmintics are substrates for Pgp of both mammals and nematodes and so we will study these interactions and assess novel and existing Pgp inhibitors for their potential to increase bioavailability in vivo.

Expected results

The understanding of these mechanisms will reduce the need for prophylactic and therapeutic use of too large doses of chemical and maximise the efficacy of treatments. This will also reduce the contamination of food and environment by diminishing the levels of anthelmintic residues. While cases have been recorded, there is as yet no unequivocal evidence that resistance of worms to commonly used anthelmintics in humans is an emerging problem. However, the use of anthelmintics in humans has increased dramatically. Helminths in humans have biological similarities to those in livestock and the anthelmintics used are the same. An important scientific challenge is to prevent the appearance of anthelmintic resistance in human helminths at an early stage.
 
Organization

The partners involved in WP 6 are (1, WP leader) INRA-Tours expert in cell biology and functional analyses applied to nematodes and in the study of resistance to anthelmintics with special reference to cellular “pumps” that eliminate the anthelmintics out the parasites; (2) INRA-Toulouse expert in relationship between pharmacokinetic of drugs in the host and efficacy of anthelmintic drugs including cellular models useful for selecting inhibitors of the efflux pumps; (3) Moredun Institute in Edinburgh engaged in the study of anthelmintic resistance particularly with regards to epidemiology, diagnosis, bioassays and molecular approach of the mechanisms of resistance.