Mechanism (biology)

Gene

World Wide Web

Philosophy

Biology

Epigenetics

Neglected tropical diseases

Leishmania

Drug resistance

Parasite hosting

Virology

Computer science

Drug

Computational biology

Drug discovery

Genetics

Leishmaniasis

Bioinformatics

Genome

Epistemology

Leishmania major

Pharmacology

Drug repositioning

Medicine

Host (biology)

Disease

Virulence

Pathology

PLoS neglected tropical diseases

The state of antileishmanial chemotherapy is strongly compromised by the emergence of drug-resistant Leishmania. The evolution of drug-resistant phenotypes has been linked to the parasites' intrinsic genome instability, with frequent gene and chromosome amplifications causing fitness gains that are directly selected by environmental factors, including the presence of antileishmanial drugs. Thus, even though the unique eukaryotic biology of Leishmania and its dependence on parasite-specific virulence factors provide valid opportunities for chemotherapeutical intervention, all strategies that target the parasite in a direct fashion are likely prone to select for resistance. Here, we review the current state of antileishmanial chemotherapy and discuss the limitations of ongoing drug discovery efforts. We finally propose new strategies that target Leishmania viability indirectly via mechanisms of host-parasite interaction, including parasite-released ectokinases and host epigenetic regulation, which modulate host cell signaling and transcriptional regulation, respectively, to establish permissive conditions for intracellular Leishmania survival.

The enemy within: Targeting host–parasite interaction for antileishmanial drug discovery