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Cladosporin, a fungal metabolite with potent blood and hepatic stage antimalarial activity targets lysyl-tRNA synthetase

Hoepfner, Dominic and McNamara, Case and Lim, Chek Shik and Studer, Christian and Riedl, Ralph and Aust, Thomas and McCormack, Susan L and Plouffe, David M and Schuierer, Sven and Plikat, Uwe and Hartmann, Nicole and Staedtler, Frank and Cotesta, Simona and Schmitt, Esther and Petersen, Frank and Supek, Frantisek and Glynne, Richard J and Tallarico, John and Porter, Jeffrey and Fishman, Mark and Bodenreider, Christophe and Diagana, Thierry Tidiane and Movva, Rao and Winzeler, Elizabeth A (2012) Cladosporin, a fungal metabolite with potent blood and hepatic stage antimalarial activity targets lysyl-tRNA synthetase. Cell Host & Microbe, 11 (6). pp. 654-663. ISSN 1931-3128

Abstract

Cladosporin, a fungal secondary metabolite, is reported to have a wide spectrum of biological activities. However, its primary target and mechanism of action is not known. Here we report that cladosporin has potent antimalarial activity and elucidate its target as the lysyl-tRNA synthetase in Saccharomyces cerevisiae (KRS1) and Plasmodium falciparum. Haploinsufficiency profiling of S. cerevisiae in the presence of cladosporin identified the krs1/KRS1 strain as hypersensitive, and over-expression of KRS1 leads to resistance. Furthermore, point mutations in the Krs1 Lysine-ATP binding-site also yield resistance. In Plasmodium falciparum addition of cladosporin rapidly inhibits protein synthesis. When plasmodial parasites were cultured in the presence of the compound to force the development of resistance, they responded by amplification of the genomic locus encoding the plasmodial lysyl-tRNA synthetase. Cladosporin inhibits both hepatic as well as blood stage parasite development, shows no cytotoxicity up to high concentrations and is thus an attractive antimalarial agent.

Item Type: Article
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Keywords: natural products, cladosporin, malaria, yeast, resistance, lysyl-tRNA synthetase, target identification
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/4585

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