The objective is to (i) study the ability of Leishmania to develop resistance to existing and new monotherapies and drug combinations, (ii) to characterize the resistant phenotypes, the stability of resistance and the cross-resistance profile of these experimentally induced or clinically resistant parasites and (iii) to explore the relevance and implementation of profiling Leishmania’s resistance within drug R&D pipelines.
Two model situations will be considered. A first model uses a retrospective approach; drugs that have been in clinical use for longer than a decade (antimonials and miltefosine) have shown decreased efficacy: could the knowledge on parasite’s resistance to these drugs (have) extend(ed) their life span? The second model implements a prospective approach by analyzing drugs that are in development: could a better knowledge of parasite’s adaptation skills to lead compounds (rapidity, metabolic pathways…) help drug developers to further optimize the compound or re-assess the ‘targetability’ of an enzyme/entire metabolic pathway?
To answer these questions, we will use a collection of clinical resistant isolates from treatment failure patients as well as experimentally induced resistant strains (to drugs used in the field and to new lead compounds). These strains will be characterized in depth by genomic and metabolomic methods in order to define bio-markers of resistance; their virulence pattern will be assessed.
Besides experimental research, this PhD thesis will involve a close interaction with industry for objective (iii).