Abstract
SummaryWith 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.
Highlights
Malaria is a significant health problem, with 225 million annual cases and nearly 3.2 billion people at risk (WHO, 2010)
A Natural Product Screen Identifies Cladosporin with Potent Antiplasmodial Activity Small molecules with activity against P. falciparum blood-stage parasites were previously identified in a phenotypic screen against a natural product library (Plouffe et al, 2008)
Out of the 12,000 natural products, 275 compounds inhibited parasite growth with 50% inhibitory concentration (IC50) values in the submicromolar range. These hits were further screened by a high-content image-based assay to determine their ability to block in vitro P. yoelii liver-stage development (Meister et al, 2011)
Summary
Malaria is a significant health problem, with 225 million annual cases and nearly 3.2 billion people at risk (WHO, 2010). Control and treatment of this disease is compounded by a lack of an effective vaccine. The emergence of multidrug-resistant parasites has compromised efficacy of many of the frontline chemotherapy treatments. There are many effective drugs (Burrows et al, 2011), endoperoxides are the only drug class for which clinically significant resistance has not been reported (Eastman and Fidock, 2009). Endoperoxides, like many antimalarials, are inactive against the asymptomatic malaria liver stages. To ensure continued malaria control, with an aim for eradication, next-generation antimalarials are required to be active against multidrug-resistant parasites and efficacious against liver- and blood-stage infections
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
