Importance of Chitin Synthesis for Fungal Growth and as a Target for Antifungal Agents

  • John E. McCullough

Abstract

The synthesis of the fungal cell wall component, chitin, has long been considered a possible target for antifungal chemotherapy (for a review see Cassone, 1986), Natural product inhibitors of chitin synthesis, the polyoxins and the nikkomycins, have been found that inhibit the growth of fungi (Bowers et al., 1974; Dahn et al., 1976; Hagenmaier et al., 1979; Isono et al., 1967, 1969). However, both the fact that these agents have not proven to be clinically useful antifungal agents and the low levels of chitin in yeast pathogens have raised questions about the importance of chitin to the fungal cell wall. Recent work on the genetics of chitin synthesis in the ascomycete Saccharomyces cerevisiae indicate that structural genes for chitin synthases may not be required for viability (Baymiller and McCullough, 1990, 1992; Bulawa and Osmond, 1990; Bulawa et al., 1986). To assess the suitability of chitin synthesis as a target for antifungal chemotherapy, this chapter reviews the current understanding of the mode of action of the polyoxins and nikkomycins and the genetics of chitin synthesis in S. cerevisiae that pertain to the question of the requirement for chitin for fungal growth. The evidence obtained from this work strongly supports the view that chitin synthesis is indeed required for S. cerevisiae viability.

Keywords

Chitosan Chitin Galactose Candida Nucleoside 

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References

  1. Au-Young J, Robbins PW (1990): Isolation of a chitin synthase gene (CHSI) from Candida albicans by expression in Saccharomyces cerevisiae. Mol Microbiol 4:197–207CrossRefGoogle Scholar
  2. Baymiller J, McCullough J (1990): Analysis of a Saccharomyces cerevisiae strain which grows without a functional CHS2 gene. 90th Annual Meeting of the Society for Microbiology May 13–17, 1990, Anaheim, CA Abstract H-133, p 176Google Scholar
  3. Baymiller J, McCullough J (1992): Identification of a Saccharomyces cerevisiae mutation that allows cells to grow without chitin synthase 1 or 2. (in press)Google Scholar
  4. Briza P, Ellinger A, Winkler G, Breitenbach M (1988): Chemical composition of yeast ascospore wall. The second outer layer consists of chitosan. J Biol Chem 263:11569–11574Google Scholar
  5. Briza P, Breitenbach M, Ellinger A, Segal J (1990): Isolation of two developmentally regulated genes involved in spore wall maturation in Saccharomyces cerevisiae. Genes Dev 4:1775–1789CrossRefGoogle Scholar
  6. Bowen AR, Chen-Wu J, Momany M, Young R, Szaniszlo PJ, Robbins PW (1992): Classification of fungal chitin synthases. Proc Natl Acad Sci 89:519–523CrossRefGoogle Scholar
  7. Bowers B, Levin G, Cabib E (1974): Effect of polyoxin D on chitin synthesis and septum formation in Saccharomyces cerevisiae. J Bacteriol 119:564–575Google Scholar
  8. Bulawa CE, CSD2, CSD3, and CSD4, genes required for chitin synthesis in yeast: The CSD2 gene product is related to chitin synthase and to developmentally regulated proteins in Rhizobium and Xenopus. (submitted)Google Scholar
  9. Bulawa CE, Osmond BC (1990): Chitin synthase I and chitin synthase II are not required for chitin synthesis in vivo in Saccharomyces cerevisiae. Proc Nat Acad Sci 87:7424–7428CrossRefGoogle Scholar
  10. Bulawa CE, Robbins PW (1989): Saccharomyces cerevisiae mutants deficient in chitin synthesis. J Cell Biochem 27(suppl 13E)Google Scholar
  11. Bulawa CE, Slater ML, Cabib E, Au-Young J, Sburlati A, Adair WL, Robbins PW (1986): The S. cerevisiae structural gene for chitin synthase is not required for chitin synthesis in vivo. Cell 46:213–225CrossRefGoogle Scholar
  12. Cabib E, Bowers B (1971): Chitin and yeast budding: localization of chitin in yeast bud scars. J Biol Chem 246:152–159Google Scholar
  13. Cabib E, Bowers B (1975): Timing and function of chitin synthesis in yeast. J Bacteriol 124:1586–1593Google Scholar
  14. Cabib E, Roberts R, Bowers B (1982): Synthesis of the yeast cell wall and its regulation. Annu Rev Biochem 51:763–793CrossRefGoogle Scholar
  15. Cabib E, Sburlati A, Bowers B, Silverman SJ (1989): Chitin synthase 1, an auxiliary enzyme for chitin synthesis in Saccharomyces cerevisiae. J Cell Biol 108:1665–1672CrossRefGoogle Scholar
  16. Cabib E (1991): Differential inhibition of chitin synthases 1 and 2 from Saccharomyces cerevisiae by polyoxin D and Nikkomycins. Antimicrob Agents Chemother 35:170–173CrossRefGoogle Scholar
  17. Cassone A, Mason RE, Kerridge D (1981): Lysis of yeast form cells of Candida albicans by echinocandin: A cytological study. Sabouradia 19Google Scholar
  18. Cassone A (1986): Cell wall of pathogenic yeasts and implications for antimycotic therapy. Drugs Exp Clin Res 12:635–643Google Scholar
  19. Chattaway FW, Holmes MR, Barlow AJE (1968): Cell wall composition of the mycelial and blastospore forms of C. albicans. J Gen Microbiol 51:367–376CrossRefGoogle Scholar
  20. Chiew YY, Shepherd MG, Sullivan PA (1980): Regulation of chitin synthesis during germ tube formation in Candida albicans. Arch Microbiol 125:97–106CrossRefGoogle Scholar
  21. Correa JU, Elango N, Polacheck I, Cabib E (1982): Endochitinase a mannanassociated enzyme from Saccharomyces cerevisiae. J Biol Chem 257:1392–1397Google Scholar
  22. Dahn U, Hagemaier H, Hohne H, Konig WA, Wolf G, Zahner H (1976): Stoffwechselprodukte von microorganismen, Mitteilung, Nikkomycin, ein neuer Hemmstoff der chitin synthase bei pilzen. Arch Microbiol 107:143–160CrossRefGoogle Scholar
  23. Duran A, Cabib E (1978): Solubilization and partial purification of yeast chitin synthase. Confirmation of the zymogenic nature of enzyme. J Biol Chem 253:4419–4425Google Scholar
  24. Duran A, Bowers B, Cabib E (1975): Chitin synthetase zymogen is attached to the yeast plasma membrane. Proc Nat Acad Sci USA 72:3952–3955CrossRefGoogle Scholar
  25. Gooday GW (1977): Biosynthesis of fungal wall: Mechanisms and implications. J Gen Microbiol 99:1–25CrossRefGoogle Scholar
  26. Gopal PK, Sullivan PA, Shepherd MG (1984): Metabolism of 14C glucose by regenerating protoplasts of Candida albicans. J Gen Microbiol 130:325–335Google Scholar
  27. Hagenmaier H, Keckeisen A, Zahner H, Konig WA (1979): Stoffwechselprodukte von mikroorganismen, 182. Aufklarung der strukter des nukleosidantioiotikums nikkomycin X, Liebigs. Ann Chem 1494–1502Google Scholar
  28. Hector RF, Zimmer BL, Pappagianis D (1990): Evaluation of nikkomycins X and Z in murine models of Coccoidiodomycosis, Histoplasmosis, and Blastomycosis. Antimicrob Agents Chemother 34:587–593CrossRefGoogle Scholar
  29. Isono K, Asahi K, Suzuki S (1969): Studies on polyoxins, antifungal antibiotics. XIII. The structure of polyoxins. J Am Chem Soc 91:7490–7505CrossRefGoogle Scholar
  30. Isono K, Nagatsu J, Kobinata K, Sasaki S, Suzuki S (1967): Studies on polyoxins, antifungal antibiotics. V. Isolation and characterization of polyoxins C, D, E, F, G, H, and I. Agric Biol Chem 31:190–199CrossRefGoogle Scholar
  31. Keller FA, Cabib E (1971): Chitin and yeast budding properties of chitin synthase from Saccharomyces carlsbergensis. J Biol Chem 246:160–166Google Scholar
  32. Mattia E, Carruba G, Angiolella L, Cassone A (1982): Induction of germ tube formation in Candida albicans: Uptake of inducer and germinative response. J Bacteriol 152:555–570Google Scholar
  33. McCarthy PJ, Troke PF, Gull K (1985): Mechanism of action of Nikkomycin and the peptide transport system of Candida albicans. J Gen Microbiol 131:775–780Google Scholar
  34. Minke R, Blackwell J (1978): The structure of a-chitin. J Mol Biol 120:167–182CrossRefGoogle Scholar
  35. Molano JB, Bowers B, Cabib E (1980): Distribution of chitin in the yeast cell wall. An ultrastructural and chemical study. J Cell Biol 85:199–212CrossRefGoogle Scholar
  36. Orlean P (1987): Two chitin synthases in Saccharomyces cerevisiae. J Biol Chem 262:5732–5739Google Scholar
  37. Ruiz-Herrera J, Bartinicki-Garcia S (1974): Synthesis of cell wall microfibrils in vitro by a soluble chitin synthase from Mucor rouxii. Science 186:357–359CrossRefGoogle Scholar
  38. Roberts RL, Bowers B, Slater ML, Cabib E (1983): Chitin synthesis and localization in cell division cycle mutants of Saccharomyces cerevisiae. Mol Cell Biol 3:922–930Google Scholar
  39. Roncero C, Valdivieso MH, Ribas JC, Duran A (1988): Isolation and characterization of mutants resistant to calcofluor white. J Bacteriol 170:1950–1954Google Scholar
  40. Ryley JF, Wilson RG, Gravestock MB, Poyser JP (1981): Experimental approaches to antifungal chemotherapy. Adv Pharmacol 17:47–56Google Scholar
  41. Sburlati A, Cabib E (1986): Chitin synthase 2, a presumptive participant in septum formation Saccharomyces cerevisae. J Biol Chem 15147–15152Google Scholar
  42. Shaw JA, Mol PC, Bowers B, Silverman SJ, Valdivieso MH, Duran A, Cabib E (1991): The function of chitin synthases 2 and 3 in the Saccharomyces cerevisiae cell cycle. J Cell Biol 114:111–123CrossRefGoogle Scholar
  43. Schekman R, Brawley V (1979): Localized deposition of chitin on the yeast cell surface in response to mating pheromone. Proc Nat Acad Sci 76:645–649CrossRefGoogle Scholar
  44. Shepherd MG (1987): Cell envelope of Candida albicans. CRC Crit Rev Microbiol 15:7–25CrossRefGoogle Scholar
  45. Silverman SJ (1989): Similar and different domains of chitin synthases 1 and 2 of S. cerevisiae: Two isozymes with distinct functions. Yeast 5:459–467CrossRefGoogle Scholar
  46. Silverman SJ, Sburlati A, Slater ML, Cabib E (1988): Chitin synthase 2 is essential for septum formation and cell division in Saccharomcyces cerevisiae. Proc Nat Acad Sci USA 85:4735–4739CrossRefGoogle Scholar
  47. Silverman SJ, Shaw JA, Cabib E (1991): Proteinase B is, indeed, not required for chitin synthase 1 function in Saccharomyces cerevisiae. Biochem Biophys Res Commun 174:204–210CrossRefGoogle Scholar
  48. Suhadolnik RI (1970): Nucleoside Antibiotics. New York: John Wiley & Sons, pp 204–210Google Scholar
  49. Sullivan PA, Yin CY, Molloy C. Templeton MD (1983): An analysis of the metabolism and cell wall composition of Candida albicans during germ tube formation. Can J Microbiol 29:1514–1525CrossRefGoogle Scholar
  50. Surarit R, Gopal PK, Shepherd MG (1988): Evidence for a glycosidic linkage between chitin and glucan in the cell wall of Candida albicans. J Gen Microbiol 134:1723–1730Google Scholar
  51. Tronchin G, Poulain D, Herbaut J, Biquet J (1981): Localization of chitin in the cell wall of Candida albicans by means of wheat germ agglutinin. Fluorescent and ultrastructural studies. Eur J Cell Biol 26:121–128Google Scholar

Copyright information

© Springer Science+Business Media New York 1992

Authors and Affiliations

  • John E. McCullough

There are no affiliations available

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