title: Sordarin inhibits fungal protein synthesis by blocking translocation differently to fusidic acid.
abstract: Sordarin derivatives are selective inhibitors of fungal protein synthesis, which specifically impair elongation factor 2 (EF-2) function. We have studied the effect of sordarin on the ribosome-dependent GTPase activity of EF-2 from Candida albicans in the absence of any other component of the translation system. The effect of sordarin turned out to be dependent both on the ratio of ribosomes to EF-2 and on the nature of the ribosomes. When the amount of EF-2 exceeded that of ribosomes sordarin inhibited the GTPase activity following an inverted bell-shaped dose-response curve, whereas when EF-2 and ribosomes were in equimolar concentrations sordarin yielded a typical sigmoidal dose-dependent inhibition. However, when ricin-treated ribosomes were used, sordarin stimulated the hydrolysis of GTP. These results were compared with those obtained with fusidic acid, showing that both drugs act in a different manner. All these data are consistent with sordarin blocking the elongation cycle at the initial steps of translocation, prior to GTP hydrolysis. In agreement with this conclusion, sordarin prevented the formation of peptidyl-[(3)H]puromycin on polysomes from Candida albicans.
authors.affiliation: Research Department, Glaxo Wellcome SA, PTM, C/Severo Ochoa 2, 28760-Tres Cantos, Madrid, Spain. jmd18916@GlaxoWellcome.co.uk
authors.forename: J M
authors.initials: JM
authors.lastname: Domínguez
authors.forename: M G
authors.initials: MG
authors.lastname: Gómez-Lorenzo
authors.forename: J J
authors.initials: JJ
authors.lastname: Martín
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans; D004305:Dose-Response Relationship, Drug; D005672:Fusidic Acid / Q000494:pharmacology; D020963:GTP Phosphohydrolase-Linked Elongation Factors / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006868:Hydrolysis; D007192:Indenes; D008954:Models, Biological; D010441:Peptide Chain Elongation, Translational / Q000187:drug effects*; D020652:Peptide Elongation Factor 2; D010445:Peptide Elongation Factors / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D011691:Puromycin / Q000378:metabolism; D012270:Ribosomes / Q000187:drug effects; D012276:Ricin / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D007192:Indenes; D020652:Peptide Elongation Factor 2; D010445:Peptide Elongation Factors; D011500:Protein Synthesis Inhibitors; C003329:sordarin; D011691:Puromycin; D005672:Fusidic Acid; D006160:Guanosine Triphosphate; D012276:Ricin; D020963:GTP Phosphohydrolase-Linked Elongation Factors