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Mechanisms of Action: Physiological Effects

Sordarins: A New Class of Antifungals with Selective Inhibition of the Protein Synthesis Elongation Cycle in Yeasts

Juan Manuel Domínguez, Valerie A. Kelly, Oonagh S. Kinsman, Michael S. Marriott, Federico Gómez de las Heras, J. Julio Martín
Juan Manuel Domínguez
Departamento de Investigación, Glaxo Wellcome S.A., 28760-Tres Cantos, Madrid, Spain, and
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Valerie A. Kelly
Glaxo Wellcome Research and Development, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, United Kingdom
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Oonagh S. Kinsman
Glaxo Wellcome Research and Development, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, United Kingdom
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Michael S. Marriott
Glaxo Wellcome Research and Development, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, United Kingdom
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Federico Gómez de las Heras
Departamento de Investigación, Glaxo Wellcome S.A., 28760-Tres Cantos, Madrid, Spain, and
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J. Julio Martín
Departamento de Investigación, Glaxo Wellcome S.A., 28760-Tres Cantos, Madrid, Spain, and
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DOI: 10.1128/AAC.42.9.2274
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    Fig. 1.

    Effect of GM160575 on protein synthesis in intactC. albicans cells. Protein synthesis was measured as the ability to incorporate [35S]methionine into actively growing C. albicans cells. The experiments were performed as described in Materials and Methods. Time zero corresponds to the moment of compound addition. The results are the means of three independent experiments performed in duplicate. ○, control; ■, 0.2 μg of GM160575 per ml; ▴, 5 μg of phenanthroline per ml; ▾, 2.5 μg of verrucarin per ml.

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    Fig. 2.

    Effect of GM160575 on RNA synthesis in intactC. albicans cells. RNA synthesis was measured as the ability to incorporate [3H]uridine into actively growingC. albicans cells. The experiments were performed as described in Materials and Methods. Time zero corresponds to the moment of compound addition. Results are the means of three independent experiments performed in duplicate. ○, control; ■, 0.2 μg of GM160575 per ml; □, 0.02 μg of GM160575 per ml; ▴, 5 μg of phenanthroline per ml; ▾, 2.5 μg of verrucarin per ml.

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    Fig. 3.

    Effect of sordarin on Phe-tRNAPhe synthetase activity in C. albicans. The experiment was performed as described in Materials and Methods. The effect of sordarin on Phe-tRNAPhe synthetase activity (white bars) is compared with the effect of the same drug on cell-free protein synthesis activity (shaded bars).

Tables

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  • Table 1.

    Chemical structures of the sordarin derivatives tested

    Table 1.
  • Table 2.

    Effect of sordarin derivatives on the cell-free protein synthesis assay (IC50s) and on cell growth (MICs)

    CompoundC. albicans2005EC. glabrata2375EC. parapsilosis2372EC. krusei2374EC. neoformans2867EIC50 (μg/ml) for rabbit reticulocytes
    IC50 (μg/ml)MIC (μg/ml)IC50(μg/ml)MIC (μg/ml)IC50 (μg/ml)MIC (μg/ml)IC50 (μg/ml)MIC (μg/ml)IC50 (μg/ml)MIC (μg/ml)
    Sordarin0.018.00.2>125>100>125>100>1250.06>125>100
    GR1354020.20.0150.8>125>100>125>100>1250.20.25>100
    GM1605750.08<0.0010.4>125>100>125>100>1250.010.25>100
    GM191519<0.0050.120.531.0100>125100>1250.005125>100
    GM193663<0.005<0.0010.0231.0>100>125>100>1250.28.0>100
    GM211676<0.0050.0010.018.0100>125100>1250.121.0>100
  • Table 3.

    Activity profiles of several protein synthesis inhibitors in cell-free systems from sordarin-sensitive and -resistantCandida species

    Compound (concn [μg/ml])% Protein synthesis activityStep inhibiteda
    C. albicansC. kruseiC. parapsilosis
    Cycloheximide (1)941525Translocation
    Verrucarin A (1)587Peptide bond formation
    Paromomycin (100)204324Translocation, peptide bond formation
    Anisomycin (1)415036Peptide bond formation
    Hygromycin (10)519067Translocation
    Puromycin (10)481816Peptide bond formation
    Emetine (100)779774Unknown
    Fusidic acid (100)7710080Translocation
    Homoharringtonine (100)23615Loading of aminoacyl-tRNA
    Sordarin (1)110094?
    • ↵a As described previously (2).

  • Table 4.

    Effect of sordarin on protein synthesis in reconstituted systems generated with sordarin-sensitive and -resistantCandida species

    Source of soluble factors% Remaining protein synthesis activity for the following ribosome sourcesa:
    C. albicansC. kruseiC. parapsilosis
    C. albicans4135
    C. krusei7996100
    C. parapsilosis8098100
    • ↵a Remaining protein synthesis activity in the presence of 0.5 μg of sordarin per ml. Each percentage is calculated with respect to the activity in the absence of sordarin for each reconstituted system.

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Sordarins: A New Class of Antifungals with Selective Inhibition of the Protein Synthesis Elongation Cycle in Yeasts
Juan Manuel Domínguez, Valerie A. Kelly, Oonagh S. Kinsman, Michael S. Marriott, Federico Gómez de las Heras, J. Julio Martín
Antimicrobial Agents and Chemotherapy Sep 1998, 42 (9) 2274-2278; DOI: 10.1128/AAC.42.9.2274

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Sordarins: A New Class of Antifungals with Selective Inhibition of the Protein Synthesis Elongation Cycle in Yeasts
Juan Manuel Domínguez, Valerie A. Kelly, Oonagh S. Kinsman, Michael S. Marriott, Federico Gómez de las Heras, J. Julio Martín
Antimicrobial Agents and Chemotherapy Sep 1998, 42 (9) 2274-2278; DOI: 10.1128/AAC.42.9.2274
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KEYWORDS

antifungal agents
Fungal Proteins
Peptide Elongation Factors
Protein Synthesis Inhibitors

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