Anti-Candida Drugs — Mechanisms of Action

  • H. Vanden Bossche
Part of the Federation of European Microbiological Societies Symposium Series book series (FEMS, volume 50)


During recent years considerable advances have been made in the identification of potential targets for antifungal agents (for a review see Kerridge and Vanden Bossche, in press). A number of them are in the cell wall, others are in the plasma membrane, endoplasmic reticulum, nucleus, mitochondria, cytoskeleton or cytosol (Fig. 1).


Candida Albicans Antifungal Agent Ergosterol Biosynthesis Squalene Epoxidase Human Pathogenic Fungus 
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  1. 1.
    G.H. Fleet, The occurence and function of endogenous wall-degrading enzymes in yeasts, in: “Microbial Cell Wall Synthesis and Autolysis”, J.R.Sabine, ed., Elsevier Science Publishers, Amsterdam, (1984).Google Scholar
  2. 2.
    M.G. Shepherd, Cell envelope of Candida albicans, CRC Crit.Rev.Microb., 15: 7 (1987).CrossRefGoogle Scholar
  3. 3.
    D.R. Soll, Candida albicans, in: “Fungal Dimorphism. With Emphasis on Fungi Pathogenic for Humans”, P.J.Szaniszlo, ed., Plenum Press, New York (1985).Google Scholar
  4. 4.
    Y.Y. Chiew, M.G. Shepherd, P.A. Sullivan, Regulation of chitin synthesis during germ-tube formation in Candida albicans, Arch Microhiol., 125: 97 (1980).CrossRefGoogle Scholar
  5. 5.
    J.M. Becker, N.L. Covert, P. Shenbagamurthi, A.S. Steinfeld, F. Naider, Polyoxin D inhibits growth of zoopathogenic fungi, Antimicrob. Agents Chemother., 23: 926 (1983).PubMedGoogle Scholar
  6. 6.
    J.-C. Yadan, M. Gonneau, P. Sarthou, F. Le Goffic, Sensitivity to nikkomycin Z in Candida albicans: role of peptide permeases. J.Bacteriol., 160: 884 (1984).PubMedGoogle Scholar
  7. 7.
    K. Barret-Bee and M. Hamilton, The detection and analysis of chitinase activity from the yeast form of Candida albicans, J.Gen.Microbiol., 130: 1857 (1987).Google Scholar
  8. 8.
    J.U. Correa, N. Elango, I. Polacheck, E. Cabib, Endochitinase, a mannan-associated enzyme from Saccharomyces cerevisiae, J.Biol. Chem., 257: 1392 (1982).PubMedGoogle Scholar
  9. 9.
    N. Elango, J.U. Correa, E. Cabib, Secretory character of yeast chitinase, J.Biol.Chem., 257: 1398 (1982).PubMedGoogle Scholar
  10. 10.
    D. Koga, A. Isogai, S. Sakuda, S. Matsumoato, A. Suzuki, S. Kimura, A. Ide, Specific inhibition of Bomhyx mori chitinase by allosamidin, Agric.Biol.Chem., 51: 471 (1987).CrossRefGoogle Scholar
  11. 11.
    M.V. Elorza, A. Murgui, H. Rico, F. Mirogall, R. Sentandreu, Formation of new cell wall by protoplasts of Candida albicans: Effect of papulacandin B, tunicamycin and nikkomycin, T.Gen.Microhiol., 133: 2315 (1987).Google Scholar
  12. 12.
    M. Debono, B.J. Abbott, J.R. Turner, L.C. Howard, R.S. Gordee, A.S. Hunt, M. Barnhart, R.M. Molloy, K.E. Willard, D. Fukuda, T.F. Butler, D.J. Zeckner, Synthesis and evaluation of LY121019, a member of a series of semisynthetic analogues of the autifungal lipopeptide echinocandin B, Ann.N.Y.Acad, Sci., 544: 152 (1988).CrossRefGoogle Scholar
  13. 13.
    R.S. Gordee, D.J. Zeckner, L.F. Ellis, A.L. Thakkar, L.C. Howard, In vitro and in vivo anti-Candida activity of LY1201019, J Antihiot., 37: 1054 (1984).CrossRefGoogle Scholar
  14. 14.
    R.S. Gordee, D.J. Zeckner, L.C. Howard, W.E. Alborn Jr., M. Debono, Anti-Candida activity and toxicology of LY121019. A novel semi-synthetic polypeptide antifungal antibiotic, Ann.N.Y.Acad.Sci., 544: 294 (1988).PubMedCrossRefGoogle Scholar
  15. 15.
    C.S.Taft, C.P.Selitrennikoff, LY121019 inhibits Neorospora crassa growth and (1–3)-β-D-glucan synthase, J.Antibiot., 51: 697 (1988).CrossRefGoogle Scholar
  16. 16.
    C.S. Taft, T. Stark, C.P. Selitrennikoff, Cilofungin (LY121019) inhibits Candida alhisans (1–3)-β-D-glucan synthase activity, Antimicrob.Agents.Chemother., 32: 1901 (1988).PubMedGoogle Scholar
  17. 17.
    J. Müller and I. Scheidecker, Immunoelectronmicroscopic studies on the influence of an echinocandin B analog on the cell wall antigenicity of Candida albicans, in: “Proceedings of the Xth Congress of the International Society for Human and Animal Mycology”, p. 152 (1988).Google Scholar
  18. 18.
    H.G. Hall, C. Myles, K.J. Pratt, J.A. Washington, Cilofungin (LY120019), an antifungal agent with specific activity against Candida albicans and Candida tropicalis, Antimicroh.Agents Chemother., 32: 1331 (1988).Google Scholar
  19. 19.
    D. Kerridge, M. Fasoli, F.J. Wayman, Drug resistance in Candida albicans and Candida glabrata, Ann.N.Y.Acad.Sci., 544: 245 (1988).PubMedCrossRefGoogle Scholar
  20. 20.
    D. Kerridge, H. Vanden Bossche, Drug discovery: a biochemist’s approach, in “Handbook of Experimental Pharmacology. Chemotherapy of Fungal Diseases”, J.F. Ryley, ed., Springer Verlag, Berlin (in press).Google Scholar
  21. 21.
    H. Vanden Bossche, G. Willemsens, P. Marichal, Anti-Candida drugs-the biochemical basis for their action, CRC Crit.Rev.Microbiol., 15: 57 (1987).CrossRefGoogle Scholar
  22. 22.
    D.Kerridge, Polyene macrolide antibiotics, in: “Aspergillus and Aspergillosis”, H. Vanden Bossche, D.W.R. Mackenzie, G. Cauwenbergh, eds., Plenum Press, New York & London (1988).Google Scholar
  23. 23.
    G. Medoff, The mechamism of action of amphotericin, in: “Aspergillus and Aspergillosis”, Vanden Bossche, D.W.R.Mackenzie, G.Cauwenbergh, eds., Plenum Press, New York & London (1988).Google Scholar
  24. 24.
    E.L. Hazen and R.H. Brown, Two antibiotics produced by a soil actinomycete, Science, 112: 423 (1950).PubMedGoogle Scholar
  25. 25.
    W. Gold, H.A. Stout, J.F. Pagano, R. Donovick, Amphotericins A and B, antifungal antibiotics produced by a streptomycete. I. In vitro studies. Antibiotics Annual., 567 (1956).Google Scholar
  26. 26.
    H. Vanden Bossche, Mode of action of pyridine, pyrimidine and azole antifungals, in “Sterol Biosynthesis Inhibitors. Pharmaceutical and Agrochemical Aspects”, D. Berg, M. Plempel, eds., Ellis Horwood Ltd., Chichester, England (1988).Google Scholar
  27. 27.
    K. Iwata, H. Yamaguchi, T. Hiratani, Mode of action of clotrimazole, Sabouraudia, 11: 158 (1973).PubMedCrossRefGoogle Scholar
  28. 28.
    J. Cope, Mode of action of miconazole on Candida albicans: effects on growth, viability and K+ release, J.Gen.Microhiol., 119: 245 (1980).Google Scholar
  29. 29.
    H. Vanden Bossche, J.M. Ruysschaert, F. Defrise-Quertain, G. Willemsens, F. Cornelissen, P. Marichal, W. Cools, J. Van Cutsem, The interaction of miconazole and ketoconazole with lipids. Biochem. Pharmacol, 32: 2175 (1982).Google Scholar
  30. 30.
    N.H. Georgopapadakou, B.A. Dix, S.A. Smith, J. Freudenberger, P.T. Funke, Effect of antifungal agents on lipid biosynthesis and membrane integrity in Candida albicans, Antimicrob.Agents Chemother., 31: 46 (1987).PubMedGoogle Scholar
  31. 31.
    H. Dahmen, H.C. Hoch, T. Staub, Differential effects of sterol inhibitors on growth, cell membrane permeability and ultrastructure of two target fungi, Cytol.Histol., 78: 1933 (1988).Google Scholar
  32. 32.
    D. Berg, K.-H. Büchel, W. Kramer, W. Plempel, H. Scheinpflug, Mechanistic studies as a tool for the development of new compounds, in: “Sterol Biosynthesis Inhibitors. Pharmaceutical and Agrochemical Aspects”, D. Berg and M. Plempel, eds., Ellis Horwood Ltd., Chichester, England (1988).Google Scholar
  33. 33.
    R. Brasseur, C. Vandenbosch, H. Vanden Bossche, J.M. Ruyschaert, Mode of insertion of miconazole, ketoconazole and deacylated ketoconazole in lipid bilayers. A conformational analysis, Biochem. Pharmacol., 32: 2175 (1983).PubMedCrossRefGoogle Scholar
  34. 34.
    R. Fears, Pharmacological control of 3-hydroxy-3-methylglutarylcoenzyme A reductase activity, in: “3-Hydroxy-3-methylglutarylcoenzyme A reductase”, J.R. Sabine, ed., CRC Press, Inc., Boca Raton, Florida (1983).Google Scholar
  35. 35.
    D. Berg, E. Regel, H.E. Harenberg, M. Plempel, Bifonazole and clotrimazole. Their mode of action and possible reason for the fungicidal behaviour of bifonazole, Arzneimittelforsch., 34: 139 (1984).PubMedGoogle Scholar
  36. 36.
    M. Bard, N.D. Lees, A.S. Burnett, R.A. Packer, Isolation and characterisation of mevinolin resistant mutants of Saccharomyces cerevisiae, J.Gen.Microbiol., 134: 1071 (1988).PubMedGoogle Scholar
  37. 37.
    C.E. Nakamura and R.H. Abeles, Mode of interaction of 3-hydroxy-3methylglutaryl coenzyme A reductase with strong binding inhibitors: compactin and related compounds, Biochemistry, 24: 1364 (1985).PubMedCrossRefGoogle Scholar
  38. 38.
    N.S. Ryder, Mechanism of action and biochemical selectivity of allylamine agents, Ann N.Y.Acad.Sci., 544: 208 (1988).PubMedCrossRefGoogle Scholar
  39. 39.
    N.S. Ryder, M.C. Dupont, I. Frank, Ergosterol biosynthesis inhibition by the thiocarbamate antifungal agents tolnaftate and tolciclate, Antimicrob. Agents Chemother., 29: 858 (1986).PubMedGoogle Scholar
  40. 40.
    H. Vanden Bossche, Biochemical targets for antifungal azole derivatives: hypothesis on the mode of action, in: “Current Topics in Medical Mycology”, Vol. 1, Springer Verlag, New York (1985).CrossRefGoogle Scholar
  41. 41.
    H. Vanden Bossche, P. Marichal, J. Gorrens, H. Geerts, P.A.J. Janssen, Mode of action studies - Basis for the search for new antifungals, Ann.N.Y.Acad.Sci. 544: 191 (1988).CrossRefGoogle Scholar
  42. 42.
    Y. Yoshida and Y. Aoyama, Interaction of azole fungicides with yeast cytochrome P. 450 which catalyzes lanosterol 14 a-demethylation, in: “In Vitro and In Vivo Evaluation of Antifungal Agents”, K. Iwata and H. Vanden Bossche, eds., Elsevier Publishers BV (Biomedical Division), Amsterdam (1986).Google Scholar
  43. 43.
    Y. Aoyama and Y. Yoshida, The 14 a-demethylation of lanosterol by a reconstituted cytochrome P-450 system from yeast microsomes, Biochem.Biophvs.Res.Commun., 85: 28 (1978).CrossRefGoogle Scholar
  44. 44.
    Y. Aoyama, Y. Yoshida, R. Sato, Yeast cytochrome P-450 catalysing lanosterol 14 a-demethylation, J.Biol.Chem., 259: 1661 (1984).PubMedGoogle Scholar
  45. 45.
    Y. Aoyama, Y. Yoshida, Y. Sonoda, Y. Sato, Metabolism of 32-hydroxy24,25-dihydrolanosterol by purified cytochrome P-45014DM from yeast. Evidence for contribution of the cytochrome to the whole process of lanosterol 14 a-demethylation, J.Biol.Chem., 262: 1239 (1987).PubMedGoogle Scholar
  46. 46.
    J.M. Trzaskos, R.T. Fischer, M.F. Favata, Mechanistic studies of lanosterol C-32 demethylation. Conditions which promote oxysterol intermediate accumulation during the demethylation process, J.Biol.Chem., 261: 16937 (1986).PubMedGoogle Scholar
  47. 47.
    A. Polak, Mode of action of 5-fluorocytosine in Aspergillus famigatus. in: “Aspergillus and Aspergillosis”, H. Vanden Bossche, D.W.R. Mackenzie, G. Cauwenbergh, eds., Plenum Press, New York & London (1988).Google Scholar
  48. 48.
    H.J. Scholer, Flucytosine, in: “Antifungal Chemotherapy,”, D.C.E. Speller, ed., J.Wiley & Sons Ltd., Chichester (1980).Google Scholar
  49. 49.
    P.S. Mamont, M.-C. Duhesne, J. Grove, P. Bey, Anti-proliferative properties of DL-a-difluoromethylornithine in cultured cells. A consequence of the irrversible inhibition of ornithine decarboxylase, Biochem.Biophys.Res.Commun., 81: 58 (1978).PubMedCrossRefGoogle Scholar
  50. 50.
    P.P. McCann, C.J. Bacchi, A.B. Clarkson, P. Bey, A. Sjoerdsma, P.J. Schester, P.D. Walzer, J.L.R. Barlow, Inhibition of polyamine synthesis by a difluoromethylornithine in African trypanosomes and Pneumocystis carinii as a basis of chemotherapy: biochemical and clinical aspects, Am.J.Trop.Med.Hyg., 35: 1153 (1986).PubMedGoogle Scholar
  51. 51.
    J.C. Edman, J.A. Kovacs, H. Masur, D.V. Santi, H.J. Elwood, M.L. Sogin, Ribosomal RNA sequence shows Pneumocystis carinii to be a member of the fungi, Nature 334: 519 (1988).PubMedCrossRefGoogle Scholar
  52. 52.
    M.A. Pfaller, T. Gerarden, J. Riley, Growth inhibition of pathogenic yeast isolates by a-difluoromethylornithine: an inhibitor of ornithine decarboxylase, Mycopathol. 98: 3 (1987).CrossRefGoogle Scholar
  53. 53.
    S.M. Boyle, N. Spiranganathan, D. Cordes, Susceptibility of Microsporum and Trichosporum species to suicide inhibitors of polyamine biosynthesis, J.Med.Vet.Mycol., 26: 227 (1988).PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • H. Vanden Bossche
    • 1
  1. 1.Department of Comparative BiochemistryJannsen Research FoundationBeerseBelgium

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