Drug Discovery: Nature’s Approach

  • Manuel Debono
  • Robert S. Gordee
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 96)


The emergence of immune deficiency diseases, such as AIDS or those that arise from the use of antitumor and organ transplantation regimens, has resulted in major increases in serious fungal infections. Amphotericin B remains the standard treatment of systemic mycoses, but its use is limited by severe toxic properties which make it imperative that safer and more effective therapies be found. Natural products, especially antibiotics from fermentation sources, have played a key role in the search for therapeutically useful drugs. Microorganisms such as the actinomycetes, isolated and cultured from the soil, have provided many useful antimicrobial agents with a wide spectrum of action. However, only a small number of antifungal agents have been discovered using these techniques. This is attributed to the difficulty of finding compounds that are selectively toxic to the eukaryotic fungal cell without causing damage to mammalian cells. Herein we will cover some of the current research in the discovery and evaluation of new antifungal agents from natural sources, and also the current methodology used in their biological evaluation as potential clinical candidates. In addition, a survey of recent natural products with antimycotic activity obtained from both soil screening and marine sources is included. Though not covered in this report, there has been recent interest in higher plants as sources of new structural prototypes for antifungal agents (CClark et al. 1987). Although the soil screen remains a major route for the discovery of new antifungal agents, intensive efforts have been undertaken to develop new methods for screening based upon mode of action. These mechanism-based tests may provide important alternatives to the more direct but capricious screen based on broth or agar dilution.


Minimum Inhibitory Concentration Candida Albicans Antifungal Agent Antifungal Compound Glucan Synthesis 
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  1. Abraham EP (1983) History of ß-lactam antibiotics. In: Demain AL, Solomon NA (eds) Antibiotics containing the ß-lactam structure. Part I, Chapter 1. Springer, Berlin Heidelberg New York, pp 1–13Google Scholar
  2. Argoudelis AD, Baczynskyj L, Kuo MT, Laborde AL, Sebek OK, Truesdell SE, Shilladay FB (1987) Arginomycin: production, isolation, characterization and structure. J Antibiot 40: 750–760PubMedGoogle Scholar
  3. Baguley BC, Römmele G, Gruner J, Wehrli W (1979) Papulacandin B: an inhibitor of glucan synthesis in yeast spheroplasts. Eur J Biochem 97: 345–351PubMedCrossRefGoogle Scholar
  4. Becker JM, Covert NL, Shenbagamurthi P, Steinfeld AS, Naider F (1983) Polyoxin D inhibits the growth of zoopathogenic fungi. Antimicrob Agents Chemother 23: 926–929PubMedGoogle Scholar
  5. Becker JM, Marcus S, Tullock J, Miller D, Krainer E, Khare RK, Naider F (1988) Use of the chitin-synthesis inhibitor nikkomycin to treat disseminated candidiasis in mice. J Infect Dis 157: 212–214PubMedCrossRefGoogle Scholar
  6. Benz F, Knüsel F, Nüesch J, Treichler H, Voser W, Nyfeler R, Keller-Schierlein W (1974) Stoffwechselprodukte von Microorganismen. 143. Echinocandin B, ein neuartiges Polypeptid-Antibiotikum aus Aspergillus nidulans var echinulatus: Isolierung und Bausteine. Helv Chim Acta 57: 2459–2477CrossRefGoogle Scholar
  7. Berdy J (1985) Screening, classification and identification of microbial products. In: Verrall MS (ed) Discovery and isolation of microbial products, Chapter 1. Ellis Horwood, Chichester, pp 9–31Google Scholar
  8. Besson F, Michel G (1987) Isolation and characterization of new iturins: iturin D and iturin E. J Antibiot 40: 437–442Google Scholar
  9. Bisacchi GS, Hockstein DR, Koster WH, Parker WL, Rathnum ML, Unger SE (1987) Xylocandin: a new complex of antifungal peptides. II. Structural studies and chemical modifications. J. Antibiot 40: 1520–1529PubMedGoogle Scholar
  10. Boeck LD, Fukuda DS, Abbott BJ, Debono M (1989) Deacylation of echinocandin B by Actinoplanes utahensis. J Antibiot 42: 382–388PubMedGoogle Scholar
  11. Boehm JC, Kingsbury WD (1986) Rapid and convenient synthesis of polyoxin peptides containing N-methylated peptide bonds. J Org Chem 51: 2307–2314CrossRefGoogle Scholar
  12. Bormann C, Huhn W, Zähner H, Rathmann R, Hahn H, König WA (1985) Metabolic products of microorganisms. 228 new nikkomycins produced by mutants of Streptomyces tendae. J Antibiot 38: 9–16PubMedGoogle Scholar
  13. Cabib E (1987) The synthesis and degradation of chitin. Adv Enzymol 59: 59–101PubMedGoogle Scholar
  14. Cabib E, Bowers B, Sburlati A, Silverman SJ (1988) Fungal cell wall synthesis: the construction of a biological structure. Microbiol Sei 5: 370–375Google Scholar
  15. Carmely S, Kashman Y (1985) Structure of swinholide A, a new macrolide from the marine sponge Candida albicans. Tetrahedron Lett 26: 511–514CrossRefGoogle Scholar
  16. Cassone A (1986) Cell wall of pathogenic yeasts and implication for antimycotic therapy. Drugs Expt Clin Res 12: 635–643Google Scholar
  17. Cassone A, Mason RE, Kerridge D (1981) Lysis of growing yeast-form cells of Candida albicans by echinocandin: a cytological study. Sabouraudia 19: 97–110PubMedCrossRefGoogle Scholar
  18. Chan WR, Tinto WF, Manchand PS, Todaro LJ (1987) Stereostructures of geodiamolides A and B, novel cyclodepsipeptides from the marine sponge Geodia sp. J Org Chem 52: 3091–3093CrossRefGoogle Scholar
  19. Clark AM, Watson ES, Ashfaq MK, Hufford CD (1987) In vivo efficacy of antifungal oxoaporphine alkaloids in experimental disseminated candidiasis. Pharm Res 4: 495–498PubMedCrossRefGoogle Scholar
  20. Cooper R, Horan AC, Gentile F, Gullo V, Loebenberg D, Marquez J, Patel M, Puar MS, Truumees I (1988) Sch 37137, a novel antifungal compound produced by a Micromonospora sp. J Antibiot 41: 13–19PubMedGoogle Scholar
  21. Crews P, Manes LV, Boehler M (1986) Jasplakinolide, a cyclodepsipeptide from the marine sponge, Jaspis sp. Tetrahedron Lett 27: 2797–2800CrossRefGoogle Scholar
  22. Debono M, Abbott BJ, Molloy RM, Fukuda DS, Hunt AH, Daupert VM, Counter FT, Ott JL, Carrell CB, Howard LC, Boeck LD, Hamill RL (1988a) Enzymatic and chemical modifications of lipopeptide antibiotic A21978C: The synthesis and evaluation of daptomycin (LY146032). J Antibiot 41: 1093–1105PubMedGoogle Scholar
  23. Debono M, Abbott BJ, Turner JR, Howard LC, Gordee RS, Hunt AS, Barnhart M, Molloy RM, Willard KE, Fukuda DS, Butler TF, Zeckner DJ (1988b) Synthesis and evaluation of LY121019, a member of a series of semi-synthetic analogues of the antifungal lipopeptide echinocandin B. Ann NY Acad Sei 544: 152–167CrossRefGoogle Scholar
  24. Debono M, Abbott BJ, Fukuda DS, Barnhart M, Willard KE, Molloy RM, Michel KH, Turner JR, Butler TF, Hunt AH (1989) Synthesis of new analogs of echino¬candin B by enzymatic deacylation and chemical reacylation of the echinocandin B peptide: synthesis of the antifungal agent cilofungin (LY121019). J Antibiot 42: 389–397PubMedGoogle Scholar
  25. Delzer J, Fiedler H, Müller H, Zähner H, Rathmann R, Ernst K, König WA (1984) New nikkomycins by mutasynthesis and directed fermentation. J Antibiot 37: 80–82PubMedGoogle Scholar
  26. Dobashi K, Naganawa H, Takahashi Y, Takita T, Takeuchi T (1988) Novel antifungal antibiotics octa-cosamicins A and B. II. The structure elucidation using various NMR spectroscopic methods. J Antibiot 41: 1533–1541PubMedGoogle Scholar
  27. Elorza MV, Murgui A, Sentandreu R (1985) Dimorphism in Candida albicans: contribution of mannoproteins to the architecture of yeast and mycelial cell walls. J Gen Microbiol 131: 2209–2216PubMedGoogle Scholar
  28. Elorza MV, Murgui A, Rico H, Miragall F, Sentandreu R (1987) Formation of a new cell wall by protoplasts of Candida albicans: effect of papulacandin B, tunicamycin and nikkomycin. J Gen Microbiol 133: 2315–2325PubMedGoogle Scholar
  29. Emmer G, Ryder NS, Grassberger MA (1985) Synthesis of new polyoxin derivatives and their activity against chitin synthase from Candida albicans. J Med Chem 28: 278–281PubMedCrossRefGoogle Scholar
  30. Fauth U, Zähner H, Mühlenfeld A, Achenbach H (1986) Galbonolides A and B — two 104 non-glycosidic antifungal macrolides. J Antibiot 39: 1760–1764PubMedGoogle Scholar
  31. Fiandor J, Garciä-Löpez M-T, De las Heras FG, Mendez-Castrillön PP (1987) Synthesis of modified polyoxins by reaction of uridine-5′-aldehyde with trimethyl- silylcyanide and amino acids. Synthesis 978–981Google Scholar
  32. Fiedler HP, Kurth R, Langharig J, Delzer J, Zähner H (1982) Nikkomycins: microbial inhibitors of chitin synthase. J Chem Tech Biotechnol 32: 271–280Google Scholar
  33. Fromtling RA, Abruzzo GK (1989) L-671,329, a new antifungal agent. III. In vitro activity, toxicity and efficacy in comparison to aculeacin. J Antibiot 42: 174–178PubMedGoogle Scholar
  34. Fusetani N (1988) Antifungal substances from marine invertebrates. Ann NY Acad Sci 544: 113–127PubMedCrossRefGoogle Scholar
  35. Gordee RS, Matthews TR (1968) Reliable technique for plating pathogenic fungi from organ homogenates. Appl Microbiol 16: 1610PubMedGoogle Scholar
  36. Gordee RS, Matthews TR (1970) Evaluation of systemic antifungal agents in X-irradiated mice. Appl Microbiol 20: 624–629PubMedGoogle Scholar
  37. Gordee RS, Simpson PJ (1967) Relationships of x irradiation to the enhancement of Candida albicans infections. J Bacteriol 94: 6–12PubMedGoogle Scholar
  38. Gordee RS, Zeckner DJ, Ellis LF, Thakkar AL, Howard LC (1984) In vitro and in vivo anti-Candida activity and toxicology of LY121019. J Antibiot 37:1054–1065Google Scholar
  39. Gordee RS, Zeckner DJ, Howard LC, Alborn WE, Debono M (1988) Anti-Candida activity and toxicology of LY121019, a novel semisynthetic polypeptide antifungal antibiotic. Ann NY Acad Sci 544: 294–309PubMedCrossRefGoogle Scholar
  40. Grieco PA, Hon YS, Perez-Medrano A (1988) A convergent, enantiospecific total synthesis of the novel cyclodepsipeptide (+)-jasplakinolide (jaspamide). J Am Chem Soc 110: 1630–1631CrossRefGoogle Scholar
  41. Hamamoto T, Seto H, Beppu T (1983) Leptomycins A and B, new antifungal anti¬biotics II. Structure elucidation. J Antibiot 36: 646–650PubMedGoogle Scholar
  42. Hegde V, Patel M, Gunnarsson I, Horan A, Marquez J, Puar M, Gullo V (1988) Two novel macrolactam antifungal antibiotics, Sch 38518 and Sch 39185, produced by Actinomadura vulgaris sp. nov.: fermentation, isolation, structure, and biological properties. 28th Intersci Conf Antimicrob Agents Chemother, Los Angeles CA, Abstr 306Google Scholar
  43. Hook DJ, More CF, Yacobucci JJ, Dubay G, O’Connor S (1987) Integrated bio-logical-physicochemical system for the identification of antitumor compounds in fermentation broths. J Chromatogr 385: 99–108PubMedCrossRefGoogle Scholar
  44. Hori M, Kakiki K, Suzuki S, Misato T (1971) Studies on the mode of action of polyoxins. III. Relation of polyoxin structure to chitin synthetase inhibition. Agric Biol Chem 35: 1280–1291CrossRefGoogle Scholar
  45. Ishibashi M, Moore RE, Patterson GML, Xu C, Clardy J (1986) Scytophycins, cytotoxic and antimycotic agents from the cyanophyte Scytonema pseudohof manni. J Org Chem 51: 5300–5306CrossRefGoogle Scholar
  46. Isono K, Nagatsu J, Kobinata K, Sasaki K, 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
  47. Isono K, Asahi K, Suzuki S (1969) Studies on polyoxins, antifungal antibiotics. XIII.Google Scholar
  48. The structure of polyoxins. J Am Chem Soc 91:7490–7505 Isono, K, Azuma T, Suzuki S (1971) Polyoxin analogs. 1. Synthesis of aminoacyl derivatives of 5′-amino-5′-deoxyuridine. Chem Pharm Bull 19: 505–512Google Scholar
  49. Iwai Y, Omura S (1982) Culture conditions for screening of new antibiotics. J Antibiot 35: 123–141PubMedGoogle Scholar
  50. Kachi H, Hattpri H, Sassa T (1986) A new antifungal substance, bromomonilicin, and its precursor produced by Monilinia fructicola. J Antibiot 39: 164–166PubMedGoogle Scholar
  51. Keller-Juslen C, Kuhn M, Loosli HR, Petcher TJ, Weber HP, von Wartburg A (1976) Struktur des cyclopeptid-antibiotikums SL 7801 (= echinocandin B). Tetrahedron Lett 4147–4150Google Scholar
  52. Kelly R, Miller SM, Kurtz MB, Kirsch DR (1988) One-step gene disruption by cotransformation to isolate double auxotrophs in Candida albicans. Mol Gen Genet 214: 24–31PubMedCrossRefGoogle Scholar
  53. Kernan MR, Faulkner DJ (1987) Halichondramide, an antifungal macrolide from the sponge Halichondria sp. Tetrahedron Lett 28: 2809–2812CrossRefGoogle Scholar
  54. Kerridge D (1986) Mode of action of clinically important antifungal drugs. In: Rose AH, Tempest DW (eds) Adv microbial physiology, vol 27. Academic, New York, pp 1–64Google Scholar
  55. Kerridge D, Fasoli M, Wayman FJ (1988) Drug resistance in Candida albicans and Candida glabrata. Ann NY Acad Sci 544: 245–259PubMedCrossRefGoogle Scholar
  56. Khare RK, Becker JM, Naider FR (1988) Synthesis and anticandidal properties of polyoxin L analogues containing a-amino fatty acids. J Med Chem 31: 650–656PubMedCrossRefGoogle Scholar
  57. King HD, Langharig J, Sanglier J J (1986) Clavamycins, new clavam antibiotics from two variants of Streptomyces hygroscopicus. I Taxonomy of the producing organisms, fermentation, and biological activities. J Antibiot 39: 510–515PubMedGoogle Scholar
  58. Kirsch DR, Lai MH (1986) A modified screen for the detection of cell wall-acting antifungal compounds. J Antibiot 39: 1620–1622PubMedGoogle Scholar
  59. Komori T, Itoh Y (1985) Chaetiacandin, a novel papulacandin. II. Structure determination. J Antibiot 38: 544–546PubMedGoogle Scholar
  60. Komori T, Yamashita M, Tsurumi Y, Kohsaka M (1985) Chaetiacandin, a novel papulacandin. I. Fermentation, isolation and characterization. J Antibiot 38: 455–459PubMedGoogle Scholar
  61. Kurusu K, Ohba K, Arai T, Fukushima (1987) New peptide antibiotics, LI-F03, F04, F05, F07 and F08, produced by Bacillus polymyxa. J Antibiot 40: 1506–1514PubMedGoogle Scholar
  62. Lakey JH, Lea EJA (1986) The role of acyl chain character and other determinants on the bilayer activity of A21978C, an acidic lipopeptide antibiotic. Biochim Biophys Acta 859: 219–226PubMedCrossRefGoogle Scholar
  63. Marriott MS (1980) Inhibition of sterol biosynthesis in Candida albicans by imidazole-containing antifungals. J Gen Microbiol 117: 253–255PubMedGoogle Scholar
  64. Matsunaga S, Fusetani N, Hashimoto K, Koseki K, Noma M (1986) Bioactive marine metabolites. Part 13. Kabiramide C, a novel antifungal macrolide from nudibranch egg masses. J Am Chem Soc 108: 847–849CrossRefGoogle Scholar
  65. Meyers E, Cooper R, Dean L, Johnson JH, Slusarchyk DS, Trejo WH, Singh PD (1985) Catacandins, novel anticandidal antibiotics of bacterial origin. J Antibiot 38: 1642–1648PubMedGoogle Scholar
  66. Mizoguchi J, Saito T, Mizuno K, Hayano K (1977) On the mode of action of a new antifungal antibiotic, aculeacin A: inhibition of cell wall synthesis in Saccharomyces cerevesiae. J Antibiot 30: 308–313PubMedGoogle Scholar
  67. Moore RE, Cheuk C, Patterson GML (1984) Hapaloindoles: new alkaloids from the blue-green alga Hapalosiphon fontinalis J Am Chem Soc 106: 6456–6457CrossRefGoogle Scholar
  68. Moore RE, Patterson GML, Mynderse JS, Barchi J Jr, Norton TR, Furusawa E, Furusawa S (1986) Toxins from cyanophytes belonging to the Scytonemat- aceae. Pure Appl Chem 58: 263–271CrossRefGoogle Scholar
  69. Moore RE, Cheuk C, Yang XQG, Patterson GML, Bonjouklian R, Smitka TA, Mynderse JS, Foster RS, Jones ND, Swartzendruber JK, Deeter JB (1987a) Hapaloindoles, antibacterial and antimycotic alkaloids from the cyanophyte Hapalosiphon fontinalis. J Org Chem 52: 1036–1043CrossRefGoogle Scholar
  70. Moore RE, Yang XQG, Patterson GML (1987b) Fontonamide and anhydrohapaloxindole A, two new alkaloids from the blue-green alga Hapalosiphon fontinalis. J Org Chem 52: 3773–3777CrossRefGoogle Scholar
  71. Mukhopadhyay T, Ganguli BN, Fehlhaber HW, Kogler H, Vertesy L (1987a) Mulundocandin, a new lipopeptide antibiotic II. Structure elucidation. J Antibiot 40: 281–289PubMedGoogle Scholar
  72. Mukhopadhyay T, Roy K, Coutinho L, Rupp RH, Ganguli BN, Fehlhaber HW (1987b) Fumifungin, a new antifungal antibiotic from Aspergillus fumigatus fresenius 1863. J Antibiot 40: 1050–1052PubMedGoogle Scholar
  73. Murgui A, Elorza MV, Sentandreu R (1986) Tunicamycin and papulacandin B inhibit incorporation of specific mannoproteins into the wall of Candida albicans regenerating protoplasts. Biochim Biophys Acta 884: 550–558PubMedCrossRefGoogle Scholar
  74. Naider F, Shenbagamurthi P, Steinfeld AS, Smith HA, Boney C, Becker JM (1983) Synthesis and biological activity of tripeptidyl polyoxins as antifungal agents. Antimicrob Agents Chemother 24: 787–796PubMedGoogle Scholar
  75. Nolan RD, Cross T (1988) Isolation and screening of actinomycetes. In: Goodfellow M, Williams ST, Mordaski M (eds) Actinomyctes in biotechnology. Academic, London, pp 1–32Google Scholar
  76. Odds FC (1979) Candida and candidosis, 1st edn. Leicester University Press, LeicesterGoogle Scholar
  77. Oka M, Nishiyama Y, Ohta S, Kamei H, Konishi M, Miyaki T, Oki T, Kawaguchi H (1988a) Glidobactins A, B and C, new antitumor antibiotics 1. Production, isolation, chemical properties and biological activity. J Antibiot 41: 1331–1337PubMedGoogle Scholar
  78. Oka M, Yaginuma K, Numata K, Konishi M, Oki T, Kawaguchi H (1988b) Glido¬bactins A, B, and C, new antitumor antibiotics. II. Structure elucidation. J Antibiot 41: 1338–1350PubMedGoogle Scholar
  79. Okami Y, Hotta K (1988) Search and discovery of new antibiotics. In: Goodfellow M, Williams ST, Mordaski M (eds) Actinomycetes in biotechnology. Academic, London, pp 33–67Google Scholar
  80. Oki T, Konishi M, Tomatsu K, Tomita K, Saitoh K, Tsunakawa M, Nishio M, Miyaki T, Kawaguchi H (1988) Pradimicin, a novel class of potent antifungal antibiotics. J Antibiot 41: 1701–1704PubMedGoogle Scholar
  81. Orlean P (1987) Two chitin synthases in Saccharomyces cerevisiae. J Biol Chem 262: 5732–5739PubMedGoogle Scholar
  82. Pastor FIJ, Valentin E, Herrero E, Sentandreu R (1984) Structure of the Saccharomyces cervisiae cell wall. Mannoproteins released by zymolyase and their contri-bution to wall architecture. Biochim Biophys Acta 802: 292–300CrossRefGoogle Scholar
  83. Polak A, Dixon DM (1987) In vitro/in vivo correlation of antifungal susceptibility testing using 5-fluorocytosine and ketoconazole as examples of two extremes. In: Fromtling RA (ed) Recent trends in the discovery, development and evaluation of antifungal agents. J R Prous, Barcelona, 45–59Google Scholar
  84. Roesener JA, Scheuer PJ (1986) Ulapualide A and B, extraordinary antitumor macrolides from nudibranch egg masses. J Am Chem Soc 108: 846–847CrossRefGoogle Scholar
  85. Roy SK, Inouye Y, Nakamura S, Furukawa J, Okuda S (1987a) Isolation, structural elucidation and biological properties of neoenactins Bl, B2, Ml and M2, neoenactin congeners. J Antibiot 40: 266–274PubMedGoogle Scholar
  86. Roy K, Mukhopadhyay T, Reddy GCS, Desikan KR, Ganguli BN (1987b) Mulundocandin, a new lipopeptide antibiotic I. Taxonomy, fermentation, isolation and characterization. J Antibiot 40: 275–280PubMedGoogle Scholar
  87. Roy K, Mukhopadhyay T, Reddy GCS, Desikan KR, Rupp RH, Ganguli BN (1988) Aranorosin, a novel antibiotic from Pseudoarachniotus roseus. I. Taxonomy, fermentation, isolation, chemical and biological properties. J Antibiot 41: 1780–1784PubMedGoogle Scholar
  88. Sassa T, Kachi H, Nukina M, Suzukiy Y (1985) Chloromonilicin, a new antifungal metabolite produced by Monilina fructicola. J Antibiot 38: 439–441PubMedGoogle Scholar
  89. Satoi S, Yagi A, Asano K, Mizuno K, Watanabe T (1977) Studies on aculeacin. II. Isolation and characterization of aculeacin B, C, D, E, F and G. J. Antibiot 30: 303–307PubMedGoogle Scholar
  90. Sawistowska-Schroder ET, Kerridge D, Perry H (1984) Echinocandin inhibition of l,3-ß-D-glucan synthase from Candida albicans. FEBS Lett 173: 134–138PubMedCrossRefGoogle Scholar
  91. Schwartz RE, Hirsch CF, Springer JP, Pettibone DJ, ¿ink DL (1987) Unusual cycloproprane-containing hapalindolinones from a cultured cyanobacterium. J Org Chem 52: 3704–3706CrossRefGoogle Scholar
  92. Schwartz RE, Giacobbe RA, Bland JA, Monaghan RL (1989) L-671,329, a new antifungal agent. I. Fermentation and isolation. J Antibiot 42: 163–167PubMedGoogle Scholar
  93. Scott VR, Boehme R, Matthews TR (1988) New class of antifungal agents: jaspla- kinolide, a cyclodepsipeptide from the marine sponge, Jaspis species. Antimicrob Agents Chemother 32: 1154–1157PubMedGoogle Scholar
  94. Selitrennikoff CP (1983) Use of a temperature-sensitive, protoplast-forming Neurospora crassa strain for the detection of antifungal antibiotics. Antimicrob Agents Chemother 23: 757–765PubMedGoogle Scholar
  95. Shadomy S, Espinel-Ingroff S, Cartwright RY (1985) Laboratory studies with antifungal agents: susceptibility tests and bioassays. In: Lenteet EH, Balows AS, Hausler WJ, Shadomy HJ (eds) Manual of clinical microbiology, 4th edn. American Society for Microbiology, Washington DC, pp 991–999Google Scholar
  96. Shenbagamurthi P, Smith HA, Becker JM, Stepfeld A, Naider F (1983) Design of anticandidal agents: synthesis and biological properties of analogues of polyoxin L. J Med Chem 26: 1518–1522PubMedCrossRefGoogle Scholar
  97. Shenbagamurthi P, Smith HA, Becker JM, Naider F (1986) Synthesis and biological properties of chitin synthetase inhibitors resistant to cellular peptidases. J Med Chem 29: 802–809PubMedCrossRefGoogle Scholar
  98. Silverman SJ, Sburlati A, Slater ML, Cabib E (1988) Chitin synthase 2 is essential for septum formation and cell division in Saccharomyces cerevisiae. Proc Natl Acad Sei USA 85: 4735–4739CrossRefGoogle Scholar
  99. Smith HA, Shenbagamurthi P, Naider FR, Kundu B, Becker JM (1986) Hydrophobic polyoxins are resistant to intracellular degradation in Candida albicans. Anti-microb Agents Chemother 29: 33–39Google Scholar
  100. Sullivan PA, Yin CY, Molloy C, Templeton MD, Shepherd MG (1983) An analysis of the metabolism and cell wall composition of Candida albicans germ-tube formation. Can J Microbiol 29: 1514–1525PubMedCrossRefGoogle Scholar
  101. 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: 1723–1730PubMedGoogle Scholar
  102. Taft CS, Selitrennikoff CP (1988) LY121Ö19 inhibits Neurospora crassa growth and (l-3)-ß-D-glucan synthase. J Antibiot 41: 697–701PubMedGoogle Scholar
  103. Taft CS, Stark T, Selitrennikoff CP (1988) Cilofungin (LY121019) inhibits Candida albicans (l–3)-ß-D-glucan synthase activity. Antimicrob Agents Chemother 32: 1901–1903PubMedGoogle Scholar
  104. Takeuchi T, Hara T, Naganawa H, Okada M, Hamada M, Umezawa H, Gomi S, Sezaki M, Kondo S (1988) New antifungal antibiotics, Benanomicins A and B from an Actinomycete. J Antibiot 41: 807–811PubMedGoogle Scholar
  105. Tanaka Y, Hirata K, Takahashi Y, Iwai Y, Omura S (1987) Globopeptin, a new antifungal peptide antibiotic. J Antibiot 40: 242–244PubMedGoogle Scholar
  106. Traxler P, Fritz H, Richter WJ (1977) Zur Struktur von Papulacandin B, einem neuen antifungischen Antibiotikum. Helv Chim Acta 60: 578–584PubMedCrossRefGoogle Scholar
  107. Traxler P, Fritz H, Fuhrer H, Richter WJ (1980) Papulacandins, a new family of antibiotics with antifungal activity. Structures of papulacandins A, B, C and D. J Antibiot 33: 967–978PubMedGoogle Scholar
  108. Traxler P, Tosch W, Zak O (1987) Papulacandins—synthesis and biological activity of papulacandin B derivatives. J Antibiot 40: 1146–1164PubMedGoogle Scholar
  109. Turner JR, Butler TF, Gordee RS, Thakkar AL (1978)A32390A, a new biologically active metabolite III. In vitro and in vivo antifungal activity. J Antibiot 31:33–37Google Scholar
  110. Ubukata M, Uramoto M, Isono K (1984) The structure of neopeptins, inhibitors of fungal cell wall biosynthesis. Tetrahedron Lett 25: 423–426CrossRefGoogle Scholar
  111. Uramoto M, Itoh Y, Sekiguchi R, Shin-Ya K, Kusakabe H, Isono K (1988) A new antifungal antibiotic, cy star gin: fermentation, isolation and characterization. J Antibiot 41: 1763–1768PubMedGoogle Scholar
  112. Vanittanakom N, Loeffler W, Koch U, Jung G (1986) Fengycin — a novel antifungal lipopeptide produced by Bacillus subtills F-29-3. J Antibiot 39: 888–901PubMedGoogle Scholar
  113. Waksman SA (1937) Associative and antagonistic effects of microorganisms. I. Historical review of antagonistic relations. Soil Sci 43: 51–68CrossRefGoogle Scholar
  114. Waksman SA (1941) Antagonistic relations of microorganisms. Bacteriol Rev 5: 231–291PubMedGoogle Scholar
  115. Waksman SA (1947) What is an antibiotic or an antibiotic substance? Mycologia 39: 565–569PubMedCrossRefGoogle Scholar
  116. Waksman SA, Lechevalier HA (1962) The search for antibiotics: screening programs. In: The actinomycetes, vol III. Antibiotics of actinomycetes, Chapter 3. Williams and Wilkins, Baltimore, pp 20–30Google Scholar
  117. Weltring KM, Turgeon BG, Yoder OC, VanEtten HD (1988) Isolation of a phyto-alexin-detoxification gene from the plant pathogenic fungus Nectria haematococca by detecting its expression in Aspergillus nidulans. Gene 68: 335–344PubMedCrossRefGoogle Scholar
  118. Wichmann CF, Liesch JM, Schwartz RE (1989) L-671, 329, a new antifungal agent. II. Structure determination. J Antibiot 42: 168–173PubMedGoogle Scholar
  119. Yamaguchi H, Hiratani T, Baba MN, Osunpii M (1985) Effect of aculeacin A, a wall–active antibiotic, on synthesis of the yeast cell wall. Microbiol Immunol 29: 609–623PubMedGoogle Scholar
  120. Zabriskie TM, Klocke JA, Ireland CM, Marcus AH, Molinski TF, Faulkner DJ, Xu C, Clardy JC (1986) Jaspamide, a modified peptide from a Jaspis sponge, with insecticidal and antifungal activity. J Am Chem Soc 108: 3123–3124CrossRefGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 1990

Authors and Affiliations

  • Manuel Debono
  • Robert S. Gordee

There are no affiliations available

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