La maitrise des pompes d'efflux, un progrès dans la lutte contre les nématodes parasites

Abstract

Efflux pump inhibitors : a progress in parasitic nematode control. Animal and human nematode infestations are controlled primarily with anthelmintics. However, their continuous administration during outbreaks represents a significant expense for livestock farms. In humans also, their high cost limits their use in poor areas where parasitic worms are most prevalent and most pathogenic. Furthermore, nematodes have developed drug resistance mechanisms, specific or not, which reduce the efficiency of treatments. Among these mechanisms, the accelerated removal of anthelmintics by efflux pumps present in cell membranes, eggshells and cuticles is a major limiting factor. This accelerated efflux is very similar to the mechanism of multidrug resistance (MDR) observed in cancer cells and protozoa. This phenomenon is all the more worrying that it applies simultaneously to several chemical families of drugs. One solution is to block the efflux pumps in parasites with inhibitors. These pumps belong to the large family of ABC transporters, which have many characteristics in common. Some have major physiological functions or protect organs from toxic agents. As much as possible, inhibitors should not have any effect on the pumps of the host and target the parasite exclusively. The diversity of these pumps is greater in nematodes than in vertebrates, and there are differences in their protein structures. Some parts of these proteins are relatively well-conserved in the animal kingdom, while other parts show little homology from one transporter to another or from one species to another. The affinity of these pumps for the substrates can vary with the mutation of a single amino acid. These differences could be used to develop inhibitors specific of nematode pumps, which could then be combined with anthelmintics.