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Cellular and Molecular Life Sciences

, Volume 71, Issue 14, pp 2651–2666 | Cite as

Activation of stress signalling pathways enhances tolerance of fungi to chemical fungicides and antifungal proteins

  • Brigitte M. E. Hayes
  • Marilyn A. Anderson
  • Ana Traven
  • Nicole L. van der WeerdenEmail author
  • Mark R. BleackleyEmail author
Review

Abstract

Fungal disease is an increasing problem in both agriculture and human health. Treatment of human fungal disease involves the use of chemical fungicides, which generally target the integrity of the fungal plasma membrane or cell wall. Chemical fungicides used for the treatment of plant disease, have more diverse mechanisms of action including inhibition of sterol biosynthesis, microtubule assembly and the mitochondrial respiratory chain. However, these treatments have limitations, including toxicity and the emergence of resistance. This has led to increased interest in the use of antimicrobial peptides for the treatment of fungal disease in both plants and humans. Antimicrobial peptides are a diverse group of molecules with differing mechanisms of action, many of which remain poorly understood. Furthermore, it is becoming increasingly apparent that stress response pathways are involved in the tolerance of fungi to both chemical fungicides and antimicrobial peptides. These signalling pathways such as the cell wall integrity and high-osmolarity glycerol pathway are triggered by stimuli, such as cell wall instability, changes in osmolarity and production of reactive oxygen species. Here we review stress signalling induced by treatment of fungi with chemical fungicides and antifungal peptides. Study of these pathways gives insight into how these molecules exert their antifungal effect and also into the mechanisms used by fungi to tolerate sub-lethal treatment by these molecules. Inactivation of stress response pathways represents a potential method of increasing the efficacy of antifungal molecules.

Keywords

Fungi Antifungal peptides Fungicides Stress signalling Hog1 Cell wall integrity 

Notes

Acknowledgments

This work was supported by a Discovery Project from the Australian Research Council (ARC, DP120102694). B. H. was supported by an Australian Postgraduate Award. Work in the A.T. lab on C. albicans is funded by the Australian National Health and Medical Research Council (NHMRC), and the Monash University Researcher Accelerator (MRA) Grant.

References

  1. 1.
    Jenssen H, Hamill P, Hancock RE (2006) Peptide antimicrobial agents. Clin Microbiol Rev 19(3):491–511PubMedPubMedCentralGoogle Scholar
  2. 2.
    Hancock REW, Lehrer R (1998) Cationic peptides: a new source of antibiotics. Trends Biotechnol 16(2):82–88PubMedGoogle Scholar
  3. 3.
    Zasloff M (2002) Antimicrobial peptides of multicellular organisms. Nature 415(6870):389–395PubMedGoogle Scholar
  4. 4.
    Oren Z, Shai Y (1998) Mode of action of linear amphipathic α-helical antimicrobial peptides. Pept Sci 47(6):451–463Google Scholar
  5. 5.
    Nicolas P (2009) Multifunctional host defense peptides: intracellular-targeting antimicrobial peptides. FEBS J 276(22):6483–6496PubMedGoogle Scholar
  6. 6.
    van der Weerden NL, Bleackley MR, Anderson MA (2013) Properties and mechanisms of action of naturally occurring antifungal peptides. Cell Mol Life Sci 70(19):3545–3570Google Scholar
  7. 7.
    Theis T, Stahl U (2004) Antifungal proteins: targets, mechanisms and prospective applications. Cell Mol Life Sci 61(4):437–455PubMedGoogle Scholar
  8. 8.
    Cudic M, Otvos L Jr (2002) Intracellular targets of antibacterial peptides. Curr Drug Targets 3(2):101–106PubMedGoogle Scholar
  9. 9.
    Nikolaou E, Agrafioti I, Stumpf M, Quinn J, Stansfield I, Brown A (2009) Phylogenetic diversity of stress signalling pathways in fungi. BMC Evol Biol 9(1):44PubMedPubMedCentralGoogle Scholar
  10. 10.
    Smith DA, Morgan BA, Quinn J (2010) Stress signalling to fungal stress-activated protein kinase pathways. FEMS Microbiol Lett 306(1):1–8PubMedPubMedCentralGoogle Scholar
  11. 11.
    Alonso-Monge R, Román E, Arana DM, Pla J, Nombela C (2009) Fungi sensing environmental stress. Clin Microbiol Infect 15:17–19PubMedGoogle Scholar
  12. 12.
    Monge RA, Román E, Nombela C, Pla J (2006) The MAP kinase signal transduction network in Candida albicans. Microbiol 152(4):905–912Google Scholar
  13. 13.
    Xu J-R (2000) MAP kinases in fungal pathogens. Fungal Genet Biol 31(3):137–152PubMedGoogle Scholar
  14. 14.
    Gustin M, Albertyn J, Alexander M, Davenport K (1998) MAP kinase pathways in the yeast Saccharomyces cerevisiae. Microbiol Mol Biol Rev 62(4):1264–1300PubMedPubMedCentralGoogle Scholar
  15. 15.
    Ernst JF, Pla J (2011) Signaling the glycoshield: maintenance of the Candida albicans cell wall. Int J Med Microbiol 301(5):378–383PubMedGoogle Scholar
  16. 16.
    Ikner A, Shiozaki K (2005) Yeast signalling pathways in the oxidative stress response. Mutat Res 569(1–2):13–27PubMedGoogle Scholar
  17. 17.
    Herrero de Dios C, Roman E, Alonso Monge R, Pla J (2010) The role of MAPK signal transduction pathways in the response to oxidative stress in the fungal pathogen Candida albicans: implications in virulence. Curr Protein Pept Sci 11(8):693–703Google Scholar
  18. 18.
    Saito H, Posas F (2012) Response to hyperosmotic stress. Genetics 192(2):289–318PubMedPubMedCentralGoogle Scholar
  19. 19.
    Navarro-García F, Eisman B, Fiuza SM, Nombela C, Pla J (2005) The MAP kinase Mkc1p is activated under different stress conditions in Candida albicans. Microbiol 151(8):2737–2749Google Scholar
  20. 20.
    Levin DE (2011) Regulation of cell wall biogenesis in Saccharomyces cerevisiae: the cell wall integrity signaling pathway. Genetics 189(4):1145–1175PubMedPubMedCentralGoogle Scholar
  21. 21.
    Blankenship JR, Fanning S, Hamaker JJ, Mitchell AP (2010) An extensive circuitry for cell wall regulation in Candida albicans. PLoS Pathog 6(2):e1000752PubMedPubMedCentralGoogle Scholar
  22. 22.
    Hirooka T, Ishii H (2013) Chemical control of plant diseases. J Gen Plant Pathol 79(6):390–401Google Scholar
  23. 23.
    Enjalbert B, Smith DA, Cornell MJ, Alam I, Nicholls S, Brown AJP, Quinn J (2006) Role of Hog-1 stress-activated protein kinase in the global transcriptional response to stress in the fungal pathogen Candida albicans. Mol Biol Cell 17:1018–1032PubMedPubMedCentralGoogle Scholar
  24. 24.
    Alonso-Monge R, Navarro-García F, Román E, Negredo AI, Eisman B, Nombela C, Pla J (2003) The Hog1 mitogen-activated protein kinase is essential in the oxidative stress response and chlamydospore formation in Candida albicans. Eukaryot Cell 2(2):351–361PubMedPubMedCentralGoogle Scholar
  25. 25.
    San José C, Monge RA, Pérez-Díaz R, Pla J, Nombela C (1996) The mitogen-activated protein kinase homolog HOG1 gene controls glycerol accumulation in the pathogenic fungus Candida albicans. J Bacteriol 178(19):5850–5852PubMedPubMedCentralGoogle Scholar
  26. 26.
    Cheetham J, Smith DA, da Silva Dantas A, Doris KS, Patterson MJ, Bruce CR, Quinn J (2007) A single MAPKKK regulates the Hog1 MAPK pathway in the pathogenic fungus Candida albicans. Mol Biol Cell 18(11):4603–4614PubMedPubMedCentralGoogle Scholar
  27. 27.
    Thomas E, Roman E, Claypool S, Manzoor N, Pla J, Panwar SL (2013) Mitochondria influences CDR1 efflux pump activity, Hog1-mediated oxidative stress pathway, iron homeostasis and ergosterol levels in Candida albicans. Antimicrob Agents Chemother 57(11):5580–5599PubMedPubMedCentralGoogle Scholar
  28. 28.
    Montañés FM, Pascual-Ahuir A, Proft M (2011) Repression of ergosterol biosynthesis is essential for stress resistance and is mediated by the Hog1 MAP kinase and the Mot3 and Rox1 transcription factors. Mol Microbiol 79(4):1008–1023PubMedGoogle Scholar
  29. 29.
    Maeda T, Takekawa M, Saito H (1995) Activation of yeast PBS2 MAPKK by MAPKKKs or by binding of an SH3-containing osmosensor. Science 269(5223):554–558PubMedGoogle Scholar
  30. 30.
    Maeda T, Wurgler-Murphy S, Saito H (1994) A two-component system that regulates an osmosensing MAP kinase cascade in yeast. Nature 369:242–245PubMedGoogle Scholar
  31. 31.
    Posas F, Wurgler-Murphy SM, Maeda T, Witten EA, Thai TC, Saito H (1996) Yeast HOG1 MAP kinase cascade is regulated by a multistep phosphorelay mechanism in the SLN1–YPD1–SSK1 “two-component” osmosensor. Cell 86(6):865–875PubMedGoogle Scholar
  32. 32.
    Jacoby T, Flanagan H, Faykin A, Seto AG, Mattison C, Ota I (1997) Two protein-tyrosine phosphatases inactivate the osmotic stress response pathway in yeast by targeting the mitogen-activated protein kinase, Hog1. J Biol Chem 272(28):17749–17755PubMedGoogle Scholar
  33. 33.
    Warmka J, Hanneman J, Lee J, Amin D, Ota I (2001) Ptc1, a type 2C Ser/Thr phosphatase, inactivates the HOG pathway by dephosphorylating the mitogen-activated protein kinase Hog1. Mol Cell Biol 21(1):51–60PubMedPubMedCentralGoogle Scholar
  34. 34.
    Arana DM, Nombela C, Alonso-Monge R, Pla J (2005) The Pbs2 MAP kinase kinase is essential for the oxidative-stress response in the fungal pathogen Candida albicans. Microbiol 151(4):1033–1049Google Scholar
  35. 35.
    Smith DA, Nicholls S, Morgan BA, Brown AJP, Quinn J (2004) A conserved stress-activated protein kinase regulates a core stress response in the human pathogen Candida albicans. Mol Biol Cell 15(9):4179–4190PubMedPubMedCentralGoogle Scholar
  36. 36.
    Ferrigno P, Posas F, Koepp D, Saito H, Silver PA (1998) Regulated nucleo/cytoplasmic exchange of HOG1 MAPK requires the importin [beta] homologs NMD5 and XPO1. EMBO J 17(19):5606–5614PubMedPubMedCentralGoogle Scholar
  37. 37.
    Vr Reiser, Ruis H, Ammerer G (1999) Kinase activity-dependent nuclear export opposes stress-induced nuclear accumulation and retention of Hog1 mitogen-activated protein kinase in the budding yeast Saccharomyces cerevisiae. Mol Biol Cell 10(4):1147–1161Google Scholar
  38. 38.
    Dixon KP, Jin-Rong X, Smirnoff N, Talbot NJ (1999) Independent signaling pathways regulate cellular turgor during hyperosmotic stress and appressorium-mediated plant infection by Magnaporthe grisea. Plant Cell 11(10):2045–2058PubMedPubMedCentralGoogle Scholar
  39. 39.
    Zhang Y, Lamm R, Pillonel C, Lam S, Xu J-R (2002) Osmoregulation and fungicide resistance: the Neurospora crassa os-2 gene encodes a HOG1 mitogen-activated protein kinase homologue. Appli Environ Microbiol 68(2):532–538Google Scholar
  40. 40.
    Kojima K, Takano Y, Yoshimi A, Tanaka C, Kikuchi T, Okuno T (2004) Fungicide activity through activation of a fungal signalling pathway. Mol Microbiol 53(6):1785–1796PubMedGoogle Scholar
  41. 41.
    Segmüller N, Ellendorf U, Tudzynski B, Tudzynski P (2007) BcSAK1, a stress-activated mitogen-activated protein kinase, is involved in vegetative differentiation and pathogenicity in Botrytis cinerea. Eukary Cell 6(2):211–221Google Scholar
  42. 42.
    Hagiwara D, Asano Y, Marui J, Yoshimi A, Mizuno T, Abe K (2009) Transcriptional profiling for Aspergillus nidulans HogA MAPK signaling pathway in response to fludioxonil and osmotic stress. Fungal Genet Biol 46(11):868–878PubMedGoogle Scholar
  43. 43.
    Nagygyörgy ED, Hornok L, Ádám AL (2011) Role of MAP kinase signaling in secondary metabolism and adaptation to abiotic/fungicide stress in Fusarium. In: Thajuddin N (ed) Fungicides—beneficial and harmful aspects. InTechWeb, Rijeka, Croatia, pp 167–178Google Scholar
  44. 44.
    Yoshimi A, Kojima K, Takano Y, Tanaka C (2005) Group III histidine kinase is a positive regulator of Hog1-type mitogen-activated protein kinase in filamentous fungi. Eukaryot Cell 4(11):1820–1828PubMedPubMedCentralGoogle Scholar
  45. 45.
    Zhang X, De Micheli M, Coleman ST, Sanglard D, Moye-Rowley WS (2000) Analysis of the oxidative stress regulation of the Candida albicans transcription factor, Cap1p. Mol Microbiol 36(3):618–629PubMedGoogle Scholar
  46. 46.
    Alarco A, Raymond M (1999) The bZip transcription factor Cap1p is involved in multidrug resistance and oxidative stress response in Candida albicans. J Bacteriol 181(3):700–708PubMedPubMedCentralGoogle Scholar
  47. 47.
    Temme N, Tudzynski P (2009) Does Botrytis cinerea ignore H2O2-induced oxidative stress during infection? Characterization of Botrytis activator protein 1. Mol Plant Microbe Interact 22(8):987–998PubMedGoogle Scholar
  48. 48.
    Guo M, Chen Y, Du Y, Dong Y, Guo W, Zhai S, Zhang H, Dong S, Zhang Z, Wang Y, Wang P, Zheng X (2011) The bZIP transcription factor MoAP1 mediates the oxidative stress response and is critical for pathogenicity of the rice blast fungus Magnaporthe oryzae. PLoS Pathog 7(2):e1001302PubMedPubMedCentralGoogle Scholar
  49. 49.
    Lev S, Hadar R, Amedeo P, Baker SE, Yoder OC, Horwitz BA (2005) Activation of an AP1-like transcription factor of the maize pathogen Cochliobolus heterostrophus in response to oxidative stress and plant signals. Eukary Cell 4(2):443–454Google Scholar
  50. 50.
    Navarro-García F, Sánchez M, Pla J, Nombela C (1995) Functional characterization of the MKC1 gene of Candida albicans, which encodes a mitogen-activated protein kinase homolog related to cell integrity. Mol Cell Biol 15(4):2197–2206PubMedPubMedCentralGoogle Scholar
  51. 51.
    Valiante V, Heinekamp T, Jain R, Härtl A, Brakhage AA (2008) The mitogen-activated protein kinase MpkA of Aspergillus fumigatus regulates cell wall signaling and oxidative stress response. Fungal Genet Biol 45(5):618–627PubMedGoogle Scholar
  52. 52.
    Kraus PR, Fox DS, Cox GM, Heitman J (2003) The Cryptococcus neoformans MAP kinase Mpk1 regulates cell integrity in response to antifungal drugs and loss of calcineurin function. Mol Microbiol 48(5):1377–1387PubMedPubMedCentralGoogle Scholar
  53. 53.
    Rui O, Hahn M (2007) The Slt2-type MAP kinase Bmp3 of Botrytis cinerea is required for normal saprotrophic growth, conidiation, plant surface sensing and host tissue colonization. Mol Plant Pathol 8(2):173–184PubMedGoogle Scholar
  54. 54.
    Hou Z, Xue C, Peng Y, Katan T, Kistler HC, Xu J-R (2002) A mitogen-activated protein kinase gene (MGV1) in Fusarium graminearum is required for female fertility, heterokaryon formation, and plant infection. Mol Plant Microbe Interact 15(11):1119–1127PubMedGoogle Scholar
  55. 55.
    Xu J-R, Staiger CJ, Hamer JE (1998) Inactivation of the mitogen-activated protein kinase Mps1 from the rice blast fungus prevents penetration of host cells but allows activation of plant defense responses. Proc Natl Acad Sci USA 95(21):12713–12718PubMedPubMedCentralGoogle Scholar
  56. 56.
    Levin D (2005) Cell wall integrity signalling in Saccharomyces cerevisiae. Microbiol Mol Biol Rev 69(2):262–291PubMedPubMedCentralGoogle Scholar
  57. 57.
    Lee K, Irie K, Watanabe Y, Araki H, Nishida E, Matsumoto K, Levin D (1993) A yeast mitogen-activated protein kinase homolog (Mpk1p) mediates signalling by protein kinase C. Mol Cell Biol 13(5):3067–3075PubMedPubMedCentralGoogle Scholar
  58. 58.
    Madden K, Sheu Y-J, Baetz K, Andrews B, Snyder M (1997) SBF cell cycle regulator as a target of the yeast PKC-MAP kinase pathway. Science 275(5307):1781–1784PubMedGoogle Scholar
  59. 59.
    Baetz K, Moffat J, Haynes J, Chang M, Andrews B (2001) Transcriptional coregulation by the cell integrity mitogen-activated protein kinase Slt2 and the cell cycle regulator Swi4. Mol Cell Biol 21(19):6515–6528PubMedPubMedCentralGoogle Scholar
  60. 60.
    Dodou E, Treisman R (1997) The Saccharomyces cerevisiae MADS-box transcription factor Rlm1 is a target for the Mpk1 mitogen-activated protein kinase pathway. Mol Cell Biol 17(4):1848–1859PubMedPubMedCentralGoogle Scholar
  61. 61.
    Jung US, Levin DE (1999) Genome-wide analysis of gene expression regulated by the yeast cell wall integrity signalling pathway. Mol Microbiol 34(5):1049–1057PubMedGoogle Scholar
  62. 62.
    Garrett-Engele P, Moilanen B, Cyert MS (1995) Calcineurin, the Ca2+/calmodulin-dependent protein phosphatase, is essential in yeast mutants with cell integrity defects and in mutants that lack a functional vacuolar H(+)-ATPase. Mol Cell Biol 15(8):4103–4114PubMedPubMedCentralGoogle Scholar
  63. 63.
    Bonilla M, Cunningham KW (2003) Mitogen-activated protein kinase stimulation of Ca2+ signaling is required for survival of endoplasmic reticulum stress in yeast. Mol Biol Cell 14(10):4296–4305PubMedPubMedCentralGoogle Scholar
  64. 64.
    Zhao C, Jung US, Garrett-Engele P, Roe T, Cyert MS, Levin DE (1998) Temperature-induced expression of yeast FKS2 is under the dual control of protein kinase C and calcineurin. Mol Cell Biol 18(2):1013–1022PubMedPubMedCentralGoogle Scholar
  65. 65.
    Cyert MS (2003) Calcineurin signaling in Saccharomyces cerevisiae: how yeast go crazy in response to stress. Biochem Biophys Res Commun 311(4):1143–1150PubMedGoogle Scholar
  66. 66.
    Muller EM, Locke EG, Cunningham KW (2001) Differential regulation of two Ca2+ influx systems by pheromone signaling in Saccharomyces cerevisiae. Genetics 159(4):1527–1538PubMedPubMedCentralGoogle Scholar
  67. 67.
    Matheos DP, Kingsbury TJ, Ahsan US, Cunningham KW (1997) Tcn1p/Crz1p, a calcineurin-dependent transcription factor that differentially regulates gene expression in Saccharomyces cerevisiae. Genes Dev 11(24):3445–3458PubMedPubMedCentralGoogle Scholar
  68. 68.
    Stathopoulos-Gerontides A, Guo JJ, Cyert MS (1999) Yeast calcineurin regulates nuclear localization of the Crz1p transcription factor through dephosphorylation. Genes Dev 13(7):798–803PubMedPubMedCentralGoogle Scholar
  69. 69.
    Cunningham KW, Fink GR (1996) Calcineurin inhibits VCX1-dependent H+/Ca2+ exchange and induces Ca2+ ATPases in Saccharomyces cerevisiae. Mol Cell Biol 16(5):2226–2237PubMedPubMedCentralGoogle Scholar
  70. 70.
    Mizunuma M, Hirata D, Miyaoka R, Miyakawa T (2001) GSK-3 kinase Mck1 and calcineurin coordinately mediate Hsl1 down-regulation by Ca2+ in budding yeast. EMBO J 20(5):1074–1085PubMedPubMedCentralGoogle Scholar
  71. 71.
    Imai J, Yahara I (2000) Role of HSP90 in salt stress tolerance via stabilization and regulation of calcineurin. Mol Cell Biol 20(24):9262–9270PubMedPubMedCentralGoogle Scholar
  72. 72.
    Singh SD, Robbins N, Zaas AK, Schell WA, Perfect JR, Cowen LE (2009) Hsp90 governs echinocandin resistance in the pathogenic yeast Candida albicans via calcineurin. PLoS Pathog 5(7):e1000532PubMedPubMedCentralGoogle Scholar
  73. 73.
    Munro CA, Selvaggini S, De Bruijn I, Walker L, Lenardon MD, Gerssen B, Milne S, Brown AJP, Gow NAR (2007) The PKC, HOG and Ca2+ signalling pathways co-ordinately regulate chitin synthesis in Candida albicans. Mol Microbiol 63(5):1399–1413PubMedPubMedCentralGoogle Scholar
  74. 74.
    Choi J, Kim Y, Kim S, Park J, Lee Y-H (2009) MoCRZ1, a gene encoding a calcineurin-responsive transcription factor, regulates fungal growth and pathogenicity of Magnaporthe oryzae. Fungal Genet Biol 46(3):243–254PubMedGoogle Scholar
  75. 75.
    Ghannoum MA, Rice LB (1999) Antifungal agents: mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance. Clin Microbiol Rev 12(4):501–517PubMedPubMedCentralGoogle Scholar
  76. 76.
    Denning DW (2003) Echinocandin antifungal drugs. Lancet 362:1142–1151PubMedGoogle Scholar
  77. 77.
    Baixench M-T, Aoun N, Desnos-Ollivier M, Garcia-Hermoso D, Bretagne S, Ramires S, Piketty C, Dannaoui E (2007) Acquired resistance to echinocandins in Candida albicans: case report and review. J Antimicrob Chemother 59(6):1076–1083PubMedGoogle Scholar
  78. 78.
    Perlin DS (2011) Current perspectives on echinocandin class drugs. Future Microbiol 6(4):441–457PubMedPubMedCentralGoogle Scholar
  79. 79.
    Walker LA, Gow NAR, Munro CA (2010) Fungal echinocandin resistance. Fungal Genet Biol 47(2):117–126PubMedPubMedCentralGoogle Scholar
  80. 80.
    Bowman SM, Free SJ (2006) The structure and synthesis of the fungal cell wall. BioEssays 28(8):799–808PubMedGoogle Scholar
  81. 81.
    Reinoso-Martín C, Schüller C, Schuetzer-Muehlbauer M, Kuchler K (2003) The yeast protein kinase C cell integrity pathway mediates tolerance to the antifungal drug caspofungin through activation of Slt2p mitogen-activated protein kinase signaling. Eukaryot Cell 2(6):1200–1210PubMedPubMedCentralGoogle Scholar
  82. 82.
    Miyazaki T, Inamine T, Yamauchi S, Nagayoshi Y, Saijo T, Izumikawa K, Seki M, Kakeya H, Yamamoto Y, Yanagihara K, Miyazaki Y, Kohno S (2010) Role of the Slt2 mitogen-activated protein kinase pathway in cell wall integrity and virulence in Candida glabrata. FEMS Yeast Res 10(3):343–352PubMedGoogle Scholar
  83. 83.
    Munro CA (2013) Chapter four—chitin and glucan, the yin and yang of the fungal cell wall, implications for antifungal drug discovery and therapy. In: Sima S, Geoffrey MG (eds) Adv Appl Microbiol, vol 83. Academic Press, London, pp 145–172Google Scholar
  84. 84.
    Walker LA, Munro CA, de Bruijn I, Lenardon MD, McKinnon A, Gow NAR (2008) Stimulation of chitin synthesis rescues Candida albicans from echinocandins. PLoS Pathog 4(4):e1000040PubMedPubMedCentralGoogle Scholar
  85. 85.
    Wiederhold NP, Kontoyiannis DP, Prince RA, Lewis RE (2005) Attenuation of the activity of caspofungin at high concentrations against Candida albicans: possible role of cell wall integrity and calcineurin pathways. Antimicrob Agents Chemother 49(12):5146–5148PubMedPubMedCentralGoogle Scholar
  86. 86.
    Gaughran JP, Lai MH, Kirsch DR, Silverman SJ (1994) Nikkomycin Z is a specific inhibitor of Saccharomyces cerevisiae chitin synthase isozyme Chs3 in vitro and in vivo. J Bacteriol 176(18):5857–5860PubMedPubMedCentralGoogle Scholar
  87. 87.
    Navarro-García F, Alonso-Monge R, Rico H, Pla J, Sentandreu R, Nombela C (1998) A role for the MAP kinase gene MKC1 in cell wall construction and morphological transitions in Candida albicans. Microbiol 144(2):411–424Google Scholar
  88. 88.
    LaFayette SL, Collins C, Zaas AK, Schell WA, Betancourt-Quiroz M, Gunatilaka AAL, Perfect JR, Cowen LE (2010) PKC signaling regulates drug resistance of the fungal pathogen Candida albicans via circuitry comprised of Mkc1, calcineurin, and Hsp90. PLoS Pathog 6(8):e1001069PubMedPubMedCentralGoogle Scholar
  89. 89.
    Kamada Y, Jung US, Piotrowski J, Levin DE (1995) The protein kinase C-activated MAP kinase pathway of Saccharomyces cerevisiae mediates a novel aspect of the heat shock response. Genes Dev 9(13):1559–1571PubMedGoogle Scholar
  90. 90.
    Sorgo AG, Heilmann CJ, Dekker HL, Bekker M, Brul S, de Koster CG, de Koning LJ, Klis FM (2011) Effects of fluconazole on the secretome, the wall proteome, and wall integrity of the clinical fungus Candida albicans. Eukaryot Cell 10(8):1071–1081PubMedPubMedCentralGoogle Scholar
  91. 91.
    Jandrositz A, Turnowsky F, Högenauer G (1991) The gene encoding squalene epoxidase from Saccharomyces cerevisiae: cloning and characterization. Gene 107(1):155–160PubMedGoogle Scholar
  92. 92.
    Marcireau C, Guilloton M, Karst F (1990) In vivo effects of fenpropimorph on the yeast Saccharomyces cerevisiae and determination of the molecular basis of the antifungal property. Antimicrob Agents Chemother 34(6):989–993PubMedPubMedCentralGoogle Scholar
  93. 93.
    Hartsel S, Bolard J (1996) Amphotericin B: new life for an old drug. Trends Pharmacol Sci 17(12):445–449PubMedGoogle Scholar
  94. 94.
    Kelly J, Rowan R, McCann M, Kavanagh K (2009) Exposure to caspofungin activates Cap and Hog pathways in Candida albicans. Med Mycol 47(7):697–706PubMedGoogle Scholar
  95. 95.
    Alonso-Monge R, Navarro-García F, Molero G, Diez-Orejas R, Gustin M, Pla J, Sánchez M, Nombela C (1999) Role of the mitogen-activated protein kinase Hog1p in morphogenesis and virulence of Candida albicans. J Bacteriol 181(10):3058–3068PubMedPubMedCentralGoogle Scholar
  96. 96.
    Torres-Quiroz F, García-Marqués S, Coria R, Randez-Gil F, Prieto JA (2010) The activity of yeast Hog1 MAPK Is required during endoplasmic reticulum stress induced by tunicamycin exposure. J Biol Chem 285(26):20088–20096PubMedPubMedCentralGoogle Scholar
  97. 97.
    Gullino ML, Leroux P, Smith CM (2000) Uses and challenges of novel compounds for plant disease control. Crop Protect 19(1):1–11Google Scholar
  98. 98.
    Pillonel C, Meyer T (1997) Effect of phenyl pyrroles on glycerol accumulation and protein kinase activity of Neurospora crassa. Pestic Sci 49:229–236Google Scholar
  99. 99.
    Yaakov G, Bell M, Hohmann S, Engelberg D (2003) Combination of two activating mutations in one HOG1 gene forms hyperactive enzymes that induce growth arrest. Mol Cell Biol 23(14):4826–4840PubMedPubMedCentralGoogle Scholar
  100. 100.
    Motoyama T, Ochiai N, Morita M, Iida Y, Usami R, Kudo T (2008) Involvement of putative response regulator genes of the rice blast fungus Magnaporthe oryzae in osmotic stress response, fungicide action, and pathogenicity. Curr Genet 54(4):185–195PubMedGoogle Scholar
  101. 101.
    Bahn Y-S, Kojima K, Cox GM, Heitman J (2005) Specialization of the HOG pathway and its impact on differentiation and virulence of Cryptococcus neoformans. Mol Biol Cell 16(5):2285–2300PubMedPubMedCentralGoogle Scholar
  102. 102.
    Kojima K, Bahn Y-S, Heitman J (2006) Calcineurin, Mpk1 and Hog1 MAPK pathways independently control fludioxonil antifungal sensitivity in Cryptococcus neoformans. Microbiol 152(3):591–604Google Scholar
  103. 103.
    Ochiai N, Fujimura M, Oshima M, Motoyama T, Ichiishi A, Yamada-Okabe H, Yamaguchi I (2002) Effects of iprodione and fludioxonil on glycerol synthesis and hyphal development in Candida albicans. Biosci Biotech Biochem 66(10):2209–2215Google Scholar
  104. 104.
    Merchan S, Bernal D, Serrano R, Yenush L (2004) Response of the Saccharomyces cerevisiae Mpk1 mitogen-activated protein kinase pathway to increases in internal turgor pressure caused by loss of Ppz protein phosphatases. Eukaryot Cell 3(1):100–107PubMedPubMedCentralGoogle Scholar
  105. 105.
    Alarco A-M, Balan I, Talibi D, Mainville N, Raymond M (1997) AP1-mediated multidrug resistance in Saccharomyces cerevisiae requires FLR1 encoding a transporter of the major facilitator superfamily. J Biol Chem 272(31):19304–19313PubMedGoogle Scholar
  106. 106.
    Schubert S, Barker KS, Znaidi S, Schneider S, Dierolf F, Dunkel N, Aïd M, Boucher G, Rogers PD, Raymond M, Morschhäuser J (2011) Regulation of efflux pump expression and drug resistance by the transcription factors Mrr1, Upc2, and Cap1 in Candida albicans. Antimicrob Agents Chemother 55(5):2212–2223PubMedPubMedCentralGoogle Scholar
  107. 107.
    Ko Y-J, Yu YM, Kim G-B, Lee G-W, Maeng PJ, Kim S, Floyd A, Heitman J, Bahn Y-S (2009) Remodeling of global transcription patterns of Cryptococcus neoformans genes mediated by the stress-activated HOG signaling pathways. Eukaryot Cell 8(8):1197–1217PubMedPubMedCentralGoogle Scholar
  108. 108.
    Thevissen K, de Mello Tavares P, Xu D, Blankenship J, Vandenbosch D, Idkowiak-Baldys J, Govaert G, Bink A, Rozental S, de Groot PW, Davis TR, Kumamoto CA, Vargas G, Nimrichter L, Coenye T, Mitchell A, Roemer T, Hannun YA, Cammue BP (2012) The plant defensin RsAFP2 induces cell wall stress, septin mislocalization and accumulation of ceramides in Candida albicans. Mol Microbiol 84(1):166–180PubMedPubMedCentralGoogle Scholar
  109. 109.
    Thevissen K, Warnecke DC, Francois IEJA, Leipelt M, Heinz E, Ott C, Zahringer U, Thomma BPHJ, Ferket KKA, Cammue BPA (2004) Defensins from insects and plants interact with fungal glucosylceramides. J Biol Chem 279(6):3900–3905PubMedGoogle Scholar
  110. 110.
    Koo JC, Lee B, Young ME, Koo SC, Cooper JA, Baek D, Lim CO, Lee SY, Yun DJ, Cho MJ (2004) Pn-AMP1, a plant defense protein, induces actin depolarization in yeasts. Plant Cell Physiol 45(11):1669–1680PubMedPubMedCentralGoogle Scholar
  111. 111.
    Hayes BME, Bleackley MR, Wiltshire JL, Anderson MA, Traven A, van der Weerden NL (2013) Identification and mechanism of action of the plant defensin NaD1 as a new member of the antifungal drug arsenal against Candida albicans. Antimicrob Agents Chemother 57(8):3667–3675PubMedPubMedCentralGoogle Scholar
  112. 112.
    Ramamoorthy V, Zhao X, Snyder AK, Xu J-R, Shah DM (2007) Two mitogen-activated protein kinase signalling cascades mediate basal resistance to antifungal plant defensins in Fusarium graminearum. Cell Microbiol 9(6):1491–1506PubMedGoogle Scholar
  113. 113.
    Jenczmionka N, Maier F, Lösch A, Schäfer W (2003) Mating, conidiation and pathogenicity of Fusarium graminearum, the main causal agent of the head-blight disease of wheat, are regulated by the MAP kinase gpmk1. Curr Genet 43(2):87–95PubMedGoogle Scholar
  114. 114.
    Hagen S, Marx F, Ram AF, Meyer V (2007) The antifungal protein AFP from Aspergillus giganteus inhibits chitin synthesis in sensitive fungi. Appl Environ Microbiol 73(7):2128–2134PubMedPubMedCentralGoogle Scholar
  115. 115.
    Ouedraogo JP, Hagen S, Spielvogel A, Engelhardt S, Meyer V (2011) Survival strategies of yeast and filamentous fungi against the antifungal protein AFP. J Biol Chem 286(16):13859–13868PubMedPubMedCentralGoogle Scholar
  116. 116.
    Vylkova S, Jang WS, Li W, Nayyar N, Edgerton M (2007) Histatin 5 initiates osmotic stress response in Candida albicans via activation of the Hog1 mitogen-activated protein kinase pathway. Eukaryot Cell 6(10):1876–1888PubMedPubMedCentralGoogle Scholar
  117. 117.
    Argimon S, Fanning S, Blankenship JR, Mitchell AP (2011) Interaction between the Candida albicans high-osmolarity glycerol (HOG) pathway and the response to human b-Defensins 2 and 3. Eukaryot Cell 10(2):272–275PubMedPubMedCentralGoogle Scholar
  118. 118.
    van der Weerden NL, Lay FT, Anderson MA (2008) The plant defensin, NaD1, enters the cytoplasm of Fusarium oxysporum hyphae. J Biol Chem 283(21):14445–14452PubMedGoogle Scholar
  119. 119.
    Aerts AM, Bammens L, Govaert G, Carmona-Gutierrez D, Madeo F, Cammue BP, Thevissen K (2011) The antifungal plant defensin HsAFP1 from Heuchera sanguinea induces apoptosis in Candida albicans. Front Microbiol 2:1–9Google Scholar
  120. 120.
    Sussman A, Huss K, Chio L-C, Heidler S, Shaw M, Ma D, Zhu G, Campbell RM, Park T-S, Kulanthaivel P, Scott JE, Carpenter JW, Strege MA, Belvo MD, Swartling JR, Fischl A, Yeh W-K, Shih C, Ye XS (2004) Discovery of cercosporamide, a known antifungal natural product, as a selective Pkc1 kinase inhibitor through high-throughput screening. Eukaryot Cell 3(4):932–943PubMedPubMedCentralGoogle Scholar
  121. 121.
    Del Poeta M, Cruz MC, Cardenas ME, Perfect JR, Heitman J (2000) Synergistic antifungal activities of bafilomycin A1, fluconazole, and the pneumocandin MK-0991/caspofungin acetate (L-743,873) with calcineurin inhibitors FK506 and L-685,818 against Cryptococcus neoformans. Antimicrob Agents Chemother 44(3):739–746PubMedPubMedCentralGoogle Scholar
  122. 122.
    Onyewu C, Blankenship JR, Del Poeta M, Heitman J (2003) Ergosterol biosynthesis inhibitors become fungicidal when combined with calcineurin inhibitors against Candida albicans, Candida glabrata, and Candida krusei. Antimicrob Agents Chemother 47(3):956–964PubMedPubMedCentralGoogle Scholar
  123. 123.
    McClean MN, Mody A, Broach JR, Ramanathan S (2007) Cross-talk and decision making in MAP kinase pathways. Nat Genet 39(3):409–414PubMedGoogle Scholar
  124. 124.
    Juvvadi PR, Gehrke C, Fortwendel JR, Lamoth F, Soderblom EJ, Cook EC, Hast MA, Asfaw YG, Moseley MA, Creamer TP, Steinbach WJ (2013) Phosphorylation of calcineurin at a novel serine-proline rich region orchestrates hyphal growth and virulence in Aspergillus fumigatus. PLoS Pathog 9(8):e1003564PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Basel 2014

Authors and Affiliations

  • Brigitte M. E. Hayes
    • 1
  • Marilyn A. Anderson
    • 1
  • Ana Traven
    • 2
  • Nicole L. van der Weerden
    • 1
    Email author
  • Mark R. Bleackley
    • 1
    Email author
  1. 1.La Trobe Institute for Molecular Science, La Trobe UniversityMelbourneAustralia
  2. 2.Department of Biochemistry and Molecular BiologyMonash UniversityClaytonAustralia

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