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Antimicrob. Agents Chemother. doi:10.1128/AAC.01603-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

A chemical genomic screen in yeast reveals a role for dipthamidation of eEF2 in inhibition of protein synthesis by sordarin

Departamento de Microbiología y Genética. Instituto de Microbiología Bioquímica. CSIC and Universidad de Salamanca. Spain; Centro de Biología Molecular "Severo Ochoa". CSIC and Universidad Autónoma de Madrid. Spain

^* To whom correspondence should be addressed. Email: miguel.remacha{at}uam.es.

	Abstract

Sordarin and its derivatives are antifungal compounds of potential clinical interest. Despite the highly conserved nature of the fungal and mammalian protein synthesis machineries, sordarin is a selective inhibitor of protein synthesis in fungal organisms. In cells sensitive to sordarin, its mode of action is through preventing the release of the translation elongation factor 2 (eEF2) during the translocation step, thus blocking protein synthesis. To further investigate the cellular components required for the effects of sordarin in fungal cells, we have used the haploid deletion collection of Saccharomyces cerevisiae to systematically identify genes whose deletion confers sensitivity or resistance to the compound. Our results indicate that genes in a number of cellular pathways previously unknown to play a role in sordarin response are involved in its growth effects on fungal cells and reveal a specific requirement for the dipthamidation pathway of cells in causing eEF2 to be sensitive to the effects of sordarin on protein synthesis. Our results underscore the importance of the powerful genomic tools developed in yeast to more comprehensively understanding the cellular mechanisms involved in the response to therapeutic agents.