Selective and Specific Inhibition of the Plasmodium falciparum Lysyl-tRNA Synthetase by the Fungal Secondary Metabolite Cladosporin

14 Jun 2012

Dominic Hoepfner, Case W. McNamara, Chek Shik Lim, Christian Studer, Ralph Riedl, Thomas Aust, Susan L. McCormack, David M. Plouffe, Stephan Meister, Sven Schuierer, Uwe Plikat, Nicole Hartmann, Frank Staedtler, Simona Cotesta, Esther K. Schmitt, Frank Petersen, Frantisek Supek, Richard J. Glynne, John A. Tallarico, Jeffrey A. Porter, Mark C. Fishman, Christophe Bodenreider, Thierry T. Diagana, N. Rao Movva, Elizabeth A. Winzler

Cell Host & Microbe

DOI:  10.1016/j.chom.2012.04.015

Summary

With renewed calls for malaria eradication, next-generation antimalarials need be active against drug-resistant parasites and efficacious against both liver- and blood-stage infections. We screened a natural product library to identify inhibitors of Plasmodium falciparum blood- and liver-stage proliferation. Cladosporin, a fungal secondary metabolite whose target and mechanism of action are not known for any species, was identified as having potent, nanomolar, antiparasitic activity against both blood and liver stages. Using postgenomic methods, including a yeast deletion strains collection, we show that cladosporin specifically inhibits protein synthesis by directly targeting P. falciparum cytosolic lysyl-tRNA synthetase. Further, cladosporin is >100-fold more potent against parasite lysyl-tRNA synthetase relative to the human enzyme, which is conferred by the identity of two amino acids within the enzyme active site. Our data indicate that lysyl-tRNA synthetase is an attractive, druggable, antimalarial target that can be selectively inhibited.

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