Abstract
Leishmania is a single-celled eukaryotic parasite afflicting millions of humans worldwide, with current therapies limited to a poor selection of drugs that mostly target elements in the parasite’s cell envelope. Here we determined the atomic resolution electron cryo-microscopy (cryo-EM) structure of the Leishmania ribosome in complex with paromomycin (PAR), a highly potent compound recently approved for treatment of the fatal visceral leishmaniasis (VL). The structure reveals the mechanism by which the drug induces its deleterious effects on the parasite. We further show that PAR interferes with several aspects of cytosolic translation, thus highlighting the cytosolic rather than the mitochondrial ribosome as the primary drug target. The results also highlight unique as well as conserved elements in the PAR-binding pocket that can serve as hotspots for the development of novel therapeutics.
Highlights
Leishmania is a single-celled eukaryotic parasite afflicting millions of humans worldwide, with current therapies limited to a poor selection of drugs that mostly target elements in the parasite’s cell envelope
There is no vaccine against leishmaniasis and the therapeutic arsenal to treat the disease is restricted by both the limited drugs available and the emergence of parasite resistance mechanisms[1]
The results reveal unique elements within the pocket that contribute to drug binding in eukaryotic microbes, and coupled to biochemical and in silico experiments highlight additional members of the AG family as potential inhibitors of leishmanial cytosolic translation
Summary
Leishmania is a single-celled eukaryotic parasite afflicting millions of humans worldwide, with current therapies limited to a poor selection of drugs that mostly target elements in the parasite’s cell envelope. Based on the similarity of key elements shared between the AG-binding pocket in bacteria and the corresponding site in the mitochondrial ribosome, namely the presence of an adenine residue at position 1408 (Supplementary Fig. 1), the mitochondrial translation machinery has been considered to be the main target for these compounds in eukaryotic parasites[5].
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