WP 4 - Mechanisms of Macrocyclic Lactone Resistance

Introduction

The macrocyclic lactones, which include drugs such as ivermectin, doramectin, moxidectin and milbemycin, are the economically most important group of anthelmintics used in veterinary medicine. Widespread resistance to these drugs, as has already occurred in parts of the Southern hemisphere, would be a serious blow to the control of gastro-intestinal nematodes in Europe. The targeted selective treatments approach being tested by PARASOL depends on knowing which drugs will be effective in any given situation. At the moment tests for macrocyclic lactone resistance are relatively slow and insensitive. New fast, sensitive and reliable tests will almost certainly be based on molecular methods, but this will require a much better understanding of the molecular basis of ML resistance than we currently have. It is the aim of WP4 to supply that understanding.

Objectives

Drug resistance is commonly associated with one of two mechanisms. Either the drug target is altered or absent altogether, so that the drug can no longer act or detoxification mechanisms are enhanced so that it the drug is removed or inactivated before it has a chance to act. We will investigate both possibilities. For the macrocyclic lactones, the targets are a group of inhibitory receptors in the nematode nervous system. The detoxification mechanism is a group of pumps that remove the drug from cells. We will investigate the properties of both the receptors and the pumps in nematodes that are susceptible and resistant to the macrocyclic lactones. In some cases, especially for Haemonchus contortus, we will also take a more general approach, looking at changes in global gene expression that might be linked with resistance.

Expected results

As a result of these experiments, we aim to have defined sequence changes for ML resistance that can be incorporated into molecular tests for resistance detection.

Organization

The partners involved in WP 4 are University of Bath (WP leader), University of Ghent, INRA-Tours, University of Veterinary Medicine Hannover, Moredun Research Institute and the Slovak Academy of Sciences.