Discussion

The eukaryotic biology of Leishmania differs considerably from its hosts thus providing ample opportunity for parasite-specific chemotherapeutical intervention. We have previously identified Leishmania-specific mechanisms of stress signaling, validated various stress kinases as novel drug targets, and discovered a series of hit compounds through target-based and phenotypic screening approaches using kinase-biased inhibitor libraries. However, all strategies that directly target parasites for chemotherapy are prone to select rapidly for drug resistance through largely unknown mechanisms of Leishmania evolutionary adaptation. Applying HTseq analysis on L. donovani clinical isolates and lab strains we uncovered chromosomal amplification coupled with haplotype selection as a main mechanisms for parasite adaptation that needs to be considered in future drug discovery efforts. To limit the emergence of drug resistance I will discuss novel strategies developed in our consortia to kill intracellular parasites in an indirect fashion by targeting pathways of host/parasite interaction that are essential for Leishmania survival.