A chemical genomic screen in Saccharomyces cerevisiae reveals a role for diphthamidation of translation elongation factor 2 in inhibition of protein synthesis by sordarin

Antimicrob Agents Chemother. 2008 May;52(5):1623-9. doi: 10.1128/AAC.01603-07. Epub 2008 Feb 19.

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 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 diphthamidation 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 (Saccharomyces cerevisiae) to more comprehensively understanding the cellular mechanisms involved in the response to therapeutic agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Electrophoresis, Polyacrylamide Gel
  • Genomics / methods
  • Indenes / pharmacology*
  • Mutation
  • Peptide Elongation Factor 2 / genetics
  • Peptide Elongation Factor 2 / metabolism*
  • Protein Biosynthesis / drug effects*
  • Protein Synthesis Inhibitors / pharmacology
  • Saccharomyces cerevisiae / drug effects*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism

Substances

  • Indenes
  • Peptide Elongation Factor 2
  • Protein Synthesis Inhibitors
  • sordarin