Involvement Of Drug Detoxification Systems In Anthelmintic Resistance In Nematods

You will be hosted in the UMR1436 INRAE/ENVT INTHERES based at the National Veterinary School of Toulouse. This research unit is dedicated to the research of therapeutic innovations for the reduction and optimization of the use of antibiotics and antiparasitics.

You will join the "Resistance to antiparasitics" axis of the Unit. The project of the INRAE/INTHERES host team is part of the global context of the rational use of anti-infectives to ensure an efficient and sustainable control of livestock parasites. The performance of anthelmintic drugs is challenged by the development of drug resistance in target organisms (e.g. nematodes). With the lack of new active products, a reasonable option is to preserve the efficacy of existing and still effective anthelmintic drugs, such as macrocyclic lactones (MLs) and in particular ivermectin (IVM) which is the most used today. Thus, it is necessary to understand the mechanisms that lead to the loss of effectiveness of drugs. In that context, the objective of the thesis project is to study the fine interaction of IVM with the detoxification systems. In particular, we are interested in efflux proteins, such as P-glycoproteins (Pgp), and in P450 cytochromes. The hypothesis is that they are involved in the mechanisms of resistance to anthelmintic drugs in nematodes by participating in the elimination of the drug. The originality of the project lies in (i) the use of fluorescent drug probes and powerful imaging tools recently developed in the laboratory to track the drug in the target organism; and (ii) the exploration of novel nematode strains recently created... The objective is to discover new therapeutic targets to restore the effectiveness of existing anthelmintic drugs.

In that context, your challenge as a PhD student will be to follow the fate of IVM in the different selected models/organisms and to look for a link with the expression of Pgps or other detoxification actors. It will lead to the development of markers to discriminate nematode lines sensitive to LMs from resistant lines.

Funding category: Financement public/privé

PHD Country: France

We are looking for a motivated individual with experience working in microbiology and/or cell culture. Skills in molecular biology/biochemistry (RT-qPCR, Western blot, HPLC, enzymatic activity...) and in confocal fluorescence microscopy are desirable. Experience in the context of resistance of an organism to a chemical compound (not necessarily nematodes) will be appreciated. You must be motivated to achieve the objectives of this thesis project by using existing technologies in the laboratory while developing original and innovative approaches.

Recommended training: Master's degree/ Engineering degree.

Knowledge required:

Experience appreciated: FACS, nematode, parasitology, statistics.

Skills sought: Motivation for research, rigor, scientific curiosity, dynamism, ability to work in a team, adaptability, autonomy, benevolence in a group.