Skip to main content
SpringerLink
Log in

Antifungal Target Selection in Aspergillus nidulans

Using Bioinformatics to Make the Difference

  • Chapter
Pathogen Genomics

Part of the book series: Infectious Disease ((ID))

Abstract

Microbes are both beneficial and detrimental to humans. They produce life-saving drugs, cause diseases, destroy crops, and contaminate feeds and foods. Although fungi do not cause outbreaks or pandemics, the incidence of fungal infections among the growing population of immunocompromised patients and the recurring establishment of drug resistance underscore the need for new drugs. A search strategy that may reveal novel targets suitable for drug development is the comparative analysis of fungal and human genomes. By comparing Aspergillus nidulans unigene ESTs to the nearly complete human genome, we found 387 nonhuman ESTs with predictable function, eight of which were essential in yeast. Moreover, phylogenetic reconstruction of a fatty-acid synthase demonstrates co-segregation of fungal alpha and beta subunits, which assemble into hetero-multimers, whereas the human polypeptide associates as a homodimer. Thus, the comparative approach identifies intrinsic differences between genomes and provides new genetic information for target selection, which may lead to drugs with reduced or no host interference.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Prade RA, Zhan D, Ayoubi P, Mort AJ. Pectins, pectinases and plant-microbe interactions. Biotechnol Genet Eng Rev 1999; 16: 361–391.

    PubMed  CAS  Google Scholar 

  2. Garber G. An overview of fungal infections. Drugs 2001; 61 (Suppl 1): 1–12.

    Article  PubMed  Google Scholar 

  3. Paladino JA. Economic justification of antimicrobial management programs: implications of antimicrobial resistance. Am J Health Syst Pharm 2000; 57 (Suppl 2): S10 – S12.

    PubMed  Google Scholar 

  4. Johnston M. The yeast genome: on the road to the Golden Age. Curr Opin Genet Dev 2000; 10: 617–623.

    Article  PubMed  CAS  Google Scholar 

  5. Dixon B. Yeast as factory and factotum. Biologist (London) 2000; 47: 15–18.

    CAS  Google Scholar 

  6. Van Belle D, Andre B. A genomic view of yeast membrane transporters. Curr Opin Cell Biol 2001; 13: 389–398.

    Article  PubMed  Google Scholar 

  7. Devaux F, Marc P, Jacq C. Transcriptomes, transcription activators and microarrays. FEBS Lett 2001; 498: 140–144.

    Article  PubMed  CAS  Google Scholar 

  8. Rolland F, Winderickx J, Thevelein JM. Glucose-sensing mechanisms in eukaryotic cells. Trends Biochem Sci 2001; 26: 310–317.

    Article  PubMed  CAS  Google Scholar 

  9. Kohlwein SD. The beauty of the yeast: live cell microscopy at the limits of optical resolution. Microsc Res Tech 2000; 51: 511–529.

    Article  PubMed  CAS  Google Scholar 

  10. Bielinsky AK, Gerbi SA. Where it all starts: eukaryotic origins of DNA replication. J Cell Sci 2001; 114: 643–651.

    PubMed  CAS  Google Scholar 

  11. Bell-Pedersen D. Understanding circadian rhythmicity in Neurospora crassa: from behavior to genes and back again. Fungal Genet Biol 2000; 29: 1–18.

    Article  PubMed  CAS  Google Scholar 

  12. Osherov N, May GS. The molecular mechanisms of conidial germination. FEMS Microbiol Lett 2001; 199: 153–160.

    Article  PubMed  CAS  Google Scholar 

  13. Ebbole DJ. Carbon catabolite repression of gene expression and conidiation in Neurospora crassa. Fungal Genet Biol 1998; 25: 15–21.

    Article  PubMed  CAS  Google Scholar 

  14. Sweeney MJ, Dobson AD. Molecular biology of mycotoxin biosynthesis. FEMS Microbiol Lett 1999; 175: 149–163.

    Article  PubMed  CAS  Google Scholar 

  15. Adams TH, Wieser JK, Yu JH. Asexual sporulation in Aspergillus nidulans. Microbiol Mol Biol Rev 1998; 62: 35–54.

    PubMed  CAS  Google Scholar 

  16. Denison SH. pH regulation of gene expression in fungi. Fungal Genet Biol 2000; 29: 61–71.

    Article  PubMed  CAS  Google Scholar 

  17. Hamer L, Pan H, Adachi K, et al. Regions of microsynteny in Magnaporthe grisea and Neurospora crassa. Fungal Genet Biol 2001; 33: 137–143.

    Article  PubMed  CAS  Google Scholar 

  18. Elewski BE. Large-scale epidemiological study of the causal agents of onychomycosis: mycological findings from the Multicenter Onychomycosis Study of Terbinafine. Arch Dermatol 1997; 133: 1317–1318.

    Article  PubMed  CAS  Google Scholar 

  19. Fridkin SK, Jarvis WR. Epidemiology of nosocomial fungal infections. Clin Microbiol Rev 1996; 9: 499–511.

    PubMed  CAS  Google Scholar 

  20. Mushegian AR, Koonin EV. A minimal gene set for cellular life derived by comparison of complete bacterial genomes. Proc Natl Acad Sci USA 1996; 93:10, 268–10, 273.

    CAS  Google Scholar 

  21. Petri MG, Konig J, Moecke HP, et al. Epidemiology of invasive mycosis in ICU patients: a prospective multicenter study in 435 non-neutropenic patients. Paul-Ehrlich Society for Chemotherapy, Divisions of Mycology and Pneumonia Research. Intensive Care Med 1997; 23: 317–325.

    Article  PubMed  CAS  Google Scholar 

  22. White TC, Marr KA, Bowden RA. Clinical, cellular, and molecular factors that contribute to anti-fungal drug resistance. Clin Microbiol Rev 1998; 11: 382–402.

    PubMed  CAS  Google Scholar 

  23. Marques SA, Robles AM, Tortorano AM, Tuculet MA, Negroni R, Mendes RP. Mycoses associated with AIDS in the Third World. Med Mycol 2000; 38 (Suppl 1): 269–279.

    PubMed  Google Scholar 

  24. Durden FM, Elewski B. Fungal infections in HIV-infected patients. Semin Cutan Med Surg 1997; 16: 200–212.

    Article  PubMed  CAS  Google Scholar 

  25. Kaplan JE, Hanson D, Dworkin MS, et al. Epidemiology of human immunodeficiency virus-associated opportunistic infections in the United States in the era of highly active antiretroviral therapy. Clin Infect Dis 2000; 30(Suppl 1:)S5–S14.

    Article  PubMed  Google Scholar 

  26. Ghannoum MA, Rice LB. Antifungal agents: mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance. Clin Microbiol Rev 1999; 12: 501–517.

    PubMed  CAS  Google Scholar 

  27. Schwartlander B, Stover J, Walker N, et al. AIDS. Resource needs for HIV/AIDS. Science 2001; 292: 2434–2436.

    Article  PubMed  CAS  Google Scholar 

  28. Rippon JW. Medical Mycology. The Pathogenic Fungi and the Pathogenic Actinomycetes. Philadelphia: WB. Saunders Company, 1988, pp. 1–9.

    Google Scholar 

  29. Speller DCE. Other Antifungal Agents. In: DCE Speller (ed.). Antifungal Chemotherapy, London: John Wiley & Sons, 1980, pp. 183–210.

    Google Scholar 

  30. Weete JD, Gandhi SR. Sterols of the phylum zygomycota: phylogenetic implications. Lipids 1997; 32: 1309–1316.

    Article  PubMed  CAS  Google Scholar 

  31. Charbonneau C, Fournier I, Dufresne S, Barwicz J, Tancrede P. The interactions of amphotericin B with various sterols in relation to its possible use in anticancer therapy. Biophys Chem 2001; 91: 125–133.

    Article  PubMed  CAS  Google Scholar 

  32. Fournier I, Barwicz J, Tancrede R The structuring effects of amphotericin B on pure and ergosterol-or cholesterol-containing dipalmitoylphosphatidylcholine bilayers: a differential scanning calorimetry study. Biochim Biophys Acta 1998; 1373: 76–86.

    Article  PubMed  CAS  Google Scholar 

  33. Moir DT, Shaw KJ, Hare RS, Vovis GF. Genomics and antimicrobial drug discovery. Antimicrob Agents Chemother 1999; 43: 439–446.

    PubMed  CAS  Google Scholar 

  34. Georgopapadakou NH. Antifungals targeted to sphingolipid synthesis: focus on inositol phosphorylceramide synthase. Expert Opin Investig Drugs 2000; 9: 1787–1796.

    Article  PubMed  CAS  Google Scholar 

  35. Chiou CC, Groll AH, Walsh TJ. New drugs and novel targets for treatment of invasive fungal infections in patients with cancer. Oncologist 2000; 5: 120–135.

    Article  PubMed  CAS  Google Scholar 

  36. DiDomenico B. Novel antifungal drugs. Curr Opin Microbiol 1999; 2: 509–515.

    Article  PubMed  CAS  Google Scholar 

  37. Klein LL, Li L. Design and preparation of cyclopeptamine antifungal agents. Curr Pharm Des 1999; 5: 57–72.

    PubMed  CAS  Google Scholar 

  38. Soteropoulos P, Vaz T, Santangelo R, et al. Molecular characterization of the plasma membrane H(+)-ATPase, an antifungal target in Cryptococcus neoformans. Antimicrob Agents Chemother 2000; 44: 2349–2355.

    Article  PubMed  CAS  Google Scholar 

  39. Cowen LE, Sanglard D, Calabrese D, Sirjusingh C, Anderson JB, Kohn LM. Evolution of drug resistance in experimental populations of Candida albicans. J Bacteriol 2000; 182: 1515–1522.

    Article  PubMed  CAS  Google Scholar 

  40. Vanden Bossche H, Dromer F, Improvisi I, Lozano-Chiu M, Rex JH, Sanglard D. Antifungal drug resistance in pathogenic fungi. Med Mycol 1998; 36 (Suppl 1): 119–128.

    Google Scholar 

  41. Moore CB, Sayers N, Mosquera J, Slaven J, Denning DW. Antifungal drug resistance in Aspergillus. J Infect 2000; 41: 203–220.

    Article  PubMed  CAS  Google Scholar 

  42. Dick JD, Merz WG, Saral R. Incidence of polyene-resistant yeasts recovered from clinical specimens. Antimicrob Agents Chemother 1980; 18: 158–163.

    Article  PubMed  CAS  Google Scholar 

  43. Bouchara JP, Zouhair R, Le Boudouil S, et al. In-vivo selection of an azole-resistant petite mutant of Candida glabrata. J Med Microbiol 2000; 49: 977–984.

    PubMed  CAS  Google Scholar 

  44. Defontaine A, Bouchara JP, Declerk P, Planchenault C, Chabasse D, Hallet JN. In-vitro resistance to azoles associated with mitochondrial DNA deficiency in Candida glabrata. J Med Microbiol 1999; 48: 663–670.

    Article  PubMed  CAS  Google Scholar 

  45. Calabrese D, Bille J, Sanglard D. A novel multidrug efflux transporter gene of the major facilitator superfamily from Candida albicans (FLU1) conferring resistance to fluconazole. Microbiology 2000; 146: 2743–2754.

    PubMed  CAS  Google Scholar 

  46. Hitchcock CA, Barrett-Bee KJ, Russell NJ. The lipid composition and permeability to azole of an azole-and polyene-resistant mutant of Candida albicans. J Med Vet Mycol 1987; 25: 29–37.

    Article  PubMed  CAS  Google Scholar 

  47. vanden Bossche H, Marichal P, Odds FC, Le Jeune L, Coene MC. Characterization of an azoleresistant Candida glabrata isolate. Antimicrob Agents Chemother 1992; 36: 2602–2610.

    Article  Google Scholar 

  48. Watson PF, Rose ME, Ellis SW, England H, Kelly SL. Defective sterol C5–6 desaturation and azole resistance: a new hypothesis for the mode of action of azole antifungals. Biochem Biophys Res Commun 1989; 164: 1170–1175.

    Article  PubMed  CAS  Google Scholar 

  49. Cardenas ME, Cruz MC, Del Poeta M, Chung N, Perfect JR, Heitman J. Antifungal activities of antineoplastic agents: Saccharomyces cerevisiae as a model system to study drug action. Clin Microbiol Rev 1999; 12: 583–611.

    PubMed  CAS  Google Scholar 

  50. Fostel J, Montgomery D, Lartey R. Comparison of responses of DNA topoisomerase I from Candida albicans and human cells to four new agents which stimulate topoisomerase-dependent DNA nicking. FEMS Microbiol Lett 1996; 138: 105 111.

    Article  PubMed  CAS  Google Scholar 

  51. Kupfer DM, Reece CA, Clifton SW, Roe BA, Prade RA. Multicellular ascomycetous fungal genomes contain more than 8000 genes. Fungal Genet Biol 1997; 21: 364–372.

    Article  PubMed  CAS  Google Scholar 

  52. Zhuo D, Zhao WD, Wright FA, et al. Assembly, annotation, and integration of UNIGENE clusters into the human genome draft. Genome Res 2001; 11: 904–918.

    Article  PubMed  CAS  Google Scholar 

  53. Schuler GD. Sequence alignment and database searching. Methods Biochem Anal 1998; 39: 145–171.

    Article  PubMed  CAS  Google Scholar 

  54. Smith TF. The art of matchmaking: sequence alignment methods and their structural implications. Structure Fold Des 1999; 7: R7–R12.

    Article  PubMed  CAS  Google Scholar 

  55. Ophir R, Itoh T, Graur D, Gojobori T. A simple method for estimating the intensity of purifying selection in protein-coding genes. Mol Biol Evol 1999; 16: 49–53.

    Article  PubMed  CAS  Google Scholar 

  56. Shah I, Hunter L. Predicting enzyme function from sequence: a systematic appraisal. Proc Int Conf Intell Syst Mol Biol 1997; 5: 276–283.

    PubMed  CAS  Google Scholar 

  57. Rost B. Twilight zone of protein sequence alignments. Protein Eng 1999; 12: 85–94.

    Article  PubMed  CAS  Google Scholar 

  58. Wilson CA, Kreychman J, Gerstein M. Assessing annotation transfer for genomics: quantifying the relations between protein sequence, structure and function through traditional and probabilistic scores. J Mol Biol 2000; 297: 233–249.

    Article  PubMed  CAS  Google Scholar 

  59. Benner SA, Gaucher EA. Evolution, language and analogy in functional genomics. Trends Genet 2001; 17: 414–418.

    Article  PubMed  CAS  Google Scholar 

  60. Selkov EJ, Grechkin Y, Mikhailova N, Salkov E. MPW: the Metabolic Pathways Database. Nucleic Acids Res 1998; 26: 43–45.

    Article  PubMed  CAS  Google Scholar 

  61. Prade RA, Ayoubi P, Krishnan S, Macwana S, Russel H. Accumulation of stress and inducer-dependent plant cell wall degrading enzymes during asexual development in Aspergillus nidulans. Genetics 2001; 157: 957–967.

    PubMed  CAS  Google Scholar 

  62. Reeds PJ. Dispensable and indispensable amino acids for humans. J Nutr 2000; 130: 1835S–1840S.

    PubMed  CAS  Google Scholar 

  63. Mewes HW, Heumann K, Kaps A, et al. MIPS: a database for genomes and protein sequences. Nucleic Acids Res 1999; 27: 44–48.

    Article  PubMed  CAS  Google Scholar 

  64. Schuller HJ, Fortsch B, Rautenstrauss B, Wolf DH, Schweizer E. Differential proteolytic sensitivity of yeast fatty acid synthetase subunits alpha and beta contributing to a balanced ratio of both fatty acid synthetase components. Eur J Biochem 1992; 203: 607–614.

    Article  PubMed  CAS  Google Scholar 

  65. Brown DW, Adams TH, Keller NP. Aspergillus has distinct fatty acid synthases for primary and secondary metabolism. Proc Natl Acad Sci USA 1996; 93:14, 873–14, 877.

    CAS  Google Scholar 

  66. Ahn JH, Walton JD. A fatty acid synthase gene in Cochliobolus carbonum required for production of HC-toxin, cyclo(D-prolyl-L-alanyl-D-alanyl-L-2-amino-9, 10-epoxi-8-oxodecanoyl). Mol Plant-Microbe Interact 1997; 10: 207–214.

    PubMed  CAS  Google Scholar 

  67. Wiesner P, Beck J, Beck KF, et al. Isolation and sequence analysis of the fatty acid synthetase FAS2 gene from Penicillium patulum. Eur J Biochem 1988; 177: 69–79.

    Article  PubMed  CAS  Google Scholar 

  68. Zhao XJ, Cihlar RL. Isolation and sequence of the Candida albicans FAS 1 gene. Gene 1994; 147: 119–124.

    Article  PubMed  CAS  Google Scholar 

  69. Wakil SJ. Fatty acid synthase, a proficient multifunctional enzyme. Biochemistry 1989; 28: 4523–4530.

    Article  PubMed  CAS  Google Scholar 

  70. Chirala SS, Kuziora MA, Spector DM, Wakil SJ. Complementation of mutations and nucleotide sequence of FAS 1 gene encoding beta subunit of yeast fatty acid synthase. J Biol Chem 1987; 262: 4231–4240.

    PubMed  CAS  Google Scholar 

  71. Kottig H, Rottner G, Beck KF, Schweizer M, Schweizer E. The pentafunctional FAS 1 genes of Saccharomyces cerevisiae and Yarrowia lipolytica are co-linear and considerably longer than previously estimated. Mol Gen Genet 1991; 226: 310–314.

    Article  PubMed  CAS  Google Scholar 

  72. Mohamed AH, Chirala SS, Mody NH, Huang WY, Wakil SJ. Primary structure of the multifunctional alpha subunit protein of yeast fatty acid synthase derived from FAS2 gene sequence. J Biol Chem 1988; 263:12, 315–12, 325.

    CAS  Google Scholar 

  73. Schweizer E, Kottig H, Regler R, Rottner G. Genetic control of Yarrowia lipolytica fatty acid synthetase biosynthesis and function. J Basic Microbiol 1988; 28: 283–292.

    Article  PubMed  CAS  Google Scholar 

  74. Tai MH, Chirala SS, Wakil SJ. Roles of Ser101, Asp236, and His237 in catalysis of thioesterase 11 and of the C-terminal region of the enzyme in its interaction with fatty acid synthase. Proc Natl Acad Sci USA 1993; 90: 1852–1856.

    Article  PubMed  CAS  Google Scholar 

  75. Alefounder PR, Baldwin SA, Perham RN, Short NJ. Cloning, sequence analysis and over-expression of the gene for the class II fructose 1,6-bisphosphate aldolase of Escherichia coli. Biochem J 1989; 257: 529–534.

    PubMed  CAS  Google Scholar 

  76. Gamblin SJ, Davies GJ, Grimes JM, Jackson RM, Littlechild JA, Watson HC. Activity and specificity of human aldolases. J Mol Biol 1991; 219: 573–576.

    Article  PubMed  CAS  Google Scholar 

  77. Ko YH, Pedersen PL, Geschwind JF. Glucose catabolism in the rabbit VX2 tumor model for liver cancer: characterization and targeting hexokinase. Cancer Lett 2001; in press.

    Google Scholar 

Download references

Authors
  1. Rosanna Pena-Muralla
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Patricia Ayoubi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marcia Graminha
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nilce M. Martinez-Rossi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Antonio Rossi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rolf A. Prade
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Infectious Diseases, Johnson and Johnson Pharmaceutical Research and Development, L. L. C., San Diego, CA, USA

    Karen Joy Shaw PhD

Rights and permissions

Reprints and permissions

Copyright information

© 2002 Humana Press Inc., Totowa, NJ

About this chapter

Cite this chapter

Pena-Muralla, R., Ayoubi, P., Graminha, M., Martinez-Rossi, N.M., Rossi, A., Prade, R.A. (2002). Antifungal Target Selection in Aspergillus nidulans . In: Shaw, K.J. (eds) Pathogen Genomics. Infectious Disease. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-172-5_14

Download citation

  • DOI: https://doi.org/10.1007/978-1-59259-172-5_14

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-4684-9683-3

  • Online ISBN: 978-1-59259-172-5

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation