白色念珠菌是人類常見病原菌之一，在黏膜或導管上形成生物膜之能力是它的重要致病特性之一。生物膜形成過程包括細胞貼附、菌絲生長、分泌細胞外基質及釋放細胞。在本研究中，我們首先分析Sfp1轉錄因子在生物膜形成所扮演之角色，當剔除SFP1基因會促使細胞比野生株更容易貼附及形成生物膜，並且會增加ALS1、ALS3和HWP1等adhesin基因的表現。本研究也證明Sfp1位在Rhb1-TOR 訊息傳遞路徑之下游。此外， Bcr1和Efg1是已知影響生物膜形成之重要轉錄因子， Efg1同時也會促使菌絲生長。當在SFP1基因剔除之情況下，同時剔除BCR1或EFG1會降低adhesin基因之表現，結果會導致生物膜形成亦急遽降低。由這些結果顯示，Sfp1會經由抑制Bcr1和Efg1對ALS1、ALS3和HWP1等adhesin基因形成負調控，進而影響生物膜之形成。
在本研究第二部分，我們著重於SFP1剔除菌株之細胞壁完整性與caspofungin 抗藥性之間的關聯。因為發現SFP1剔除菌株之貼附能力較野生菌株為佳，因此我們進行分析SFP1剔除菌株細胞壁之特性。由結果發現SFP1剔除菌株之醣類含量及厚度均較野生菌株上升，而且SFP1剔除菌株的細胞壁醣類β-1,3-glucan 合成酶FKS1之表現量較野生菌株亦明顯增加，這些原因使得SFP1剔除菌株細胞壁完整性提高進而對於細胞壁抑制劑caspofungin之敏感性顯著降低。並且SFP1剔除菌株之CAS5基因表現亦較多，此亦可能幫助菌株較易抵抗藥物而存活。另外，caspofungin 可幾乎完全抑制野生菌株生物膜之形成，但SFP1剔除菌株不僅較易形成生物膜且對於caspofungin之抗藥性亦較野生株為佳。最後，發現有一些對於caspofungin敏感性降低之臨床菌株，當SFP1表現過量時會增加這些菌株對caspofungin之敏感性，這顯示Sfp1在臨床對於caspofungin 之抗藥性上應有扮演一定之角色。

Candida albicans is a major human fungal pathogen. One of the important features of C. albicans pathogenicity is the ability to form biofilms on mucosal surfaces and indwelling medical devices. Biofilm formation involves complex processes in C. albicans, including cell adhesion, filamentous growth, extracellular matrix secretion and cell dispersion. In this work, we characterized the role of the transcription factor Sfp1, particularly with respect to its function in the regulation of biofilm formation. The deletion of the SFP1 gene enhanced cell adhesion and biofilm formation in comparison to the wild type strain. Interestingly, the sfp1-deleted mutant also exhibited an increase in the expression of the ALS1, ALS3 and HWP1 genes, which encode adhesin proteins. In addition, Sfp1 was demonstrated to function downstream of the Rhb1-TOR signaling pathway. Bcr1 and Efg1 are transcription factors that are critical for controlling biofilm formation, and Efg1 is also required for hyphal growth. Deleting either the BCR1 or EFG1 gene in the sfp1-null background led to reduced adhesin gene expression. As a result, the bcr1/sfp1 or efg1/sfp1 double deletion mutants exhibited dramatically reduced biofilm formation. The results indicated that Sfp1 negatively regulates the ALS1, ALS3 and HWP1 adhesin genes and that the repression of these genes is mediated by the inhibition of Bcr1 and Efg1.
In the second part of this study, we focused on the relationship among Sfp1, cell wall integrity and resistance to caspofungin, a cell wall inhibiting drug. Because the adhesion ability of the sfp1△/sfp1△ strain is better than wild type, the cell wall properties were investigated. Our studies revealed that the polysaccharide contents and thickness of the cell wall in the sfp1△/sfp1△ mutant are increased compared to wild type. Moreover, the sfp1△/sfp1△ strain exhibited up-regulation of the expression of FKS1, which encodes β-1, 3-glucan synthase. The results also showed that the sfp1△/sfp1△ strain increases cell wall integrity to reduce the susceptibility of caspofungin. Furthermore, the sfp1△/sfp1△ strain had a higher CAS5 gene expression to protect cells from damage. Deletion of the CAS5 gene in the sfp1△/sfp1△ background caused the cells to be hypersensitive to caspofungin. Although caspofungin had a high candidacidal activity against C. albicans planktonic and biofilm cells, the sfp1△/sfp1△ mutant not only enhanced its biofilm formation but also increased caspofungin resistance. Finally, several C. albicans clinical isolates reduced caspofungin susceptibility compared to the laboratory wild type strain. Interestingly, these clinical isolates became more susceptibility to caspofungin when SFP1 was overexpressed. These data suggest that Sfp1 may also play a role in caspofungin drug resistance in the clinics.

1. Pfaller MA, Diekema DJ (2007) Epidemiology of invasive candidiasis: a persistent public health problem. Clin Microbiol Rev 20: 133-163.
2. Macphail GL, Taylor GD, Buchanan-Chell M, Ross C, Wilson S, et al. (2002) Epidemiology, treatment and outcome of candidemia: a five-year review at three Canadian hospitals. Mycoses 45: 141-145.
3. Hiller E, Zavrel M, Hauser N, Sohn K, Burger-Kentischer A, et al. (2011) Adaptation, adhesion and invasion during interaction of Candida albicans with the host--focus on the function of cell wall proteins. Int J Med Microbiol 301: 384-389.
4. Chaffin WL (2008) Candida albicans cell wall proteins. Microbiol Mol Biol Rev 72: 495-544.
5. Dalle F, Wachtler B, L'Ollivier C, Holland G, Bannert N, et al. (2010) Cellular interactions of Candida albicans with human oral epithelial cells and enterocytes. Cell Microbiol 12: 248-271.
6. Zhu W, Filler SG (2010) Interactions of Candida albicans with epithelial cells. Cell Microbiol 12: 273-282.
7. Lan CY, Newport G, Murillo LA, Jones T, Scherer S, et al. (2002) Metabolic specialization associated with phenotypic switching in Candidaalbicans. Proc Natl Acad Sci U S A 99: 14907-14912.
8. Morschhauser J (2010) Regulation of white-opaque switching in Candida albicans. Med Microbiol Immunol 199: 165-172.
9. Soll DR (2009) Why does Candida albicans switch? FEMS Yeast Res 9: 973-989.
10. Douglas LJ (2003) Candida biofilms and their role in infection. Trends Microbiol 11: 30-36.
11. Nobile CJ, Mitchell AP (2006) Genetics and genomics of Candida albicans biofilm formation. Cell Microbiol 8: 1382-1391.
12. Ramage G, Saville SP, Thomas DP, Lopez-Ribot JL (2005) Candida biofilms: an update. Eukaryot Cell 4: 633-638.
13. Kojic EM, Darouiche RO (2004) Candida infections of medical devices. Clin Microbiol Rev 17: 255-267.
14. Douglas LJ (2002) Medical importance of biofilms in Candida infections. Rev Iberoam Micol 19: 139-143.
15. Hajjeh RA, Sofair AN, Harrison LH, Lyon GM, Arthington-Skaggs BA, et al. (2004) Incidence of bloodstream infections due to Candida species and in vitro susceptibilities of isolates collected from 1998 to 2000 in a population-based active surveillance program. J Clin Microbiol 42: 1519-1527.
16. Crump JA, Collignon PJ (2000) Intravascular catheter-associated infections. Eur J Clin Microbiol Infect Dis 19: 1-8.
17. Viudes A, Peman J, Canton E, Ubeda P, Lopez-Ribot JL, et al. (2002) Candidemia at a tertiary-care hospital: epidemiology, treatment, clinical outcome and risk factors for death. Eur J Clin Microbiol Infect Dis 21: 767-774.
18. Ramage G, Mowat E, Jones B, Williams C, Lopez-Ribot J (2009) Our current understanding of fungal biofilms. Crit Rev Microbiol 35: 340-355.
19. Finkel JS, Mitchell AP (2011) Genetic control of Candida albicans biofilm development. Nat Rev Microbiol 9: 109-118.
20. Wilson LS, Reyes CM, Stolpman M, Speckman J, Allen K, et al. (2002) The direct cost and incidence of systemic fungal infections. Value Health 5: 26-34.
21. Blankenship JR, Mitchell AP (2006) How to build a biofilm: a fungal perspective. Curr Opin Microbiol 9: 588-594.
22. Nett J, Andes D (2006) Candida albicans biofilm development, modeling a host-pathogen interaction. Curr Opin Microbiol 9: 340-345.
23. Nett J, Lincoln L, Marchillo K, Massey R, Holoyda K, et al. (2007) Putative role of beta-1,3 glucans in Candida albicans biofilm resistance. Antimicrob Agents Chemother 51: 510-520.
24. Al-Fattani MA, Douglas LJ (2006) Biofilm matrix of Candida albicans and Candida tropicalis: chemical composition and role in drug resistance. J Med Microbiol 55: 999-1008.
25. Chandra J, Kuhn DM, Mukherjee PK, Hoyer LL, McCormick T, et al. (2001) Biofilm formation by the fungal pathogen Candida albicans: development, architecture, and drug resistance. J Bacteriol 183: 5385-5394.
26. Andes D, Nett J, Oschel P, Albrecht R, Marchillo K, et al. (2004) Development and characterization of an in vivo central venous catheter Candida albicans biofilm model. Infect Immun 72: 6023-6031.
27. de Groot PW, Bader O, de Boer AD, Weig M, Chauhan N (2013) Adhesins in human fungal pathogens: glue with plenty of stick. Eukaryot Cell 12: 470-481.
28. Long X, Ortiz-Vega S, Lin Y, Avruch J (2005) Rheb binding to mammalian target of rapamycin (mTOR) is regulated by amino acid sufficiency. J Biol Chem 280: 23433-23436.
29. Tsao CC, Chen YT, Lan CY (2009) A small G protein Rhb1 and a GTPase-activating protein Tsc2 involved in nitrogen starvation-induced morphogenesis and cell wall integrity of Candida albicans. Fungal Genet Biol 46: 126-136.
30. Rohde JR, Bastidas R, Puria R, Cardenas ME (2008) Nutritional control via Tor signaling in Saccharomyces cerevisiae. Curr Opin Microbiol 11: 153-160.
31. Otsubo Y, Yamamato M (2008) TOR signaling in fission yeast. Crit Rev Biochem Mol Biol 43: 277-283.
32. Loewith R, Jacinto E, Wullschleger S, Lorberg A, Crespo JL, et al. (2002) Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell 10: 457-468.
33. Bastidas RJ, Heitman J, Cardenas ME (2009) The protein kinase Tor1 regulates adhesin gene expression in Candida albicans. PLoS Pathog 5: e1000294.
34. Perlin DS (2015) Mechanisms of echinocandin antifungal drug resistance. Ann N Y Acad Sci 1354: 1-11.
35. Denning DW (2003) Echinocandin antifungal drugs. Lancet 362: 1142-1151.
36. Cleveland AA, Farley MM, Harrison LH, Stein B, Hollick R, et al. (2012) Changes in incidence and antifungal drug resistance in candidemia: results from population-based laboratory surveillance in Atlanta and Baltimore, 2008-2011. Clin Infect Dis 55: 1352-1361.
37. Katiyar S, Pfaller M, Edlind T (2006) Candida albicans and Candida glabrata clinical isolates exhibiting reduced echinocandin susceptibility. Antimicrob Agents Chemother 50: 2892-2894.
38. Garcia-Effron G, Park S, Perlin DS (2009) Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: implications for interpretive breakpoints. Antimicrob Agents Chemother 53: 112-122.
39. Reinoso-Martin C, Schuller 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: 1200-1210.
40. Walker LA, Gow NA, Munro CA (2010) Fungal echinocandin resistance. Fungal Genet Biol 47: 117-126.
41. Munro CA, Selvaggini S, de Bruijn I, Walker L, Lenardon MD, et al. (2007) The PKC, HOG and Ca2+ signalling pathways co-ordinately regulate chitin synthesis in Candida albicans. Mol Microbiol 63: 1399-1413.
42. Bruno VM, Kalachikov S, Subaran R, Nobile CJ, Kyratsous C, et al. (2006) Control of the C. albicans cell wall damage response by transcriptional regulator Cas5. PLoS Pathog 2: e21.
43. Nobile CJ, Fox EP, Nett JE, Sorrells TR, Mitrovich QM, et al. (2012) A recently evolved transcriptional network controls biofilm development in Candida albicans. Cell 148: 126-138.
44. Wang YC, Lan CY, Hsieh WP, Murillo LA, Agabian N, et al. (2010) Global screening of potential Candida albicans biofilm-related transcription factors via network comparison. BMC Bioinformatics 11: 53.
45. Loza L, Fu Y, Ibrahim AS, Sheppard DC, Filler SG, et al. (2004) Functional analysis of the Candida albicans ALS1 gene product. Yeast 21: 473-482.
46. Staab JF, Bradway SD, Fidel PL, Sundstrom P (1999) Adhesive and mammalian transglutaminase substrate properties of Candida albicans Hwp1. Science 283: 1535-1538.
47. Zhao X, Daniels KJ, Oh SH, Green CB, Yeater KM, et al. (2006) Candida albicans Als3p is required for wild-type biofilm formation on silicone elastomer surfaces. Microbiology 152: 2287-2299.
48. Reuss O, Vik A, Kolter R, Morschhauser J (2004) The SAT1 flipper, an optimized tool for gene disruption in Candida albicans. Gene 341: 119-127.
49. Park YN, Morschhauser J (2005) Tetracycline-inducible gene expression and gene deletion in Candida albicans. Eukaryot Cell 4: 1328-1342.
50. Hsu PC, Yang CY, Lan CY (2011) Candida albicans Hap43 is a repressor induced under low-iron conditions and is essential for iron-responsive transcriptional regulation and virulence. Eukaryot Cell 10: 207-225.
51. Russell CL, Brown AJ (2005) Expression of one-hybrid fusions with Staphylococcus aureus lexA in Candida albicans confirms that Nrg1 is a transcriptional repressor and that Gcn4 is a transcriptional activator. Fungal Genet Biol 42: 676-683.
52. Nailis H, Coenye T, Van Nieuwerburgh F, Deforce D, Nelis HJ (2006) Development and evaluation of different normalization strategies for gene expression studies in Candida albicans biofilms by real-time PCR. BMC Mol Biol 7: 25.
53. Hsu PC, Chao CC, Yang CY, Ye YL, Liu FC, et al. (2013) Diverse Hap43-independent functions of the Candida albicans CCAAT-binding complex. Eukaryot Cell 12: 804-815.
54. Ramage G, Vandewalle K, Wickes BL, Lopez-Ribot JL (2001) Characteristics of biofilm formation by Candida albicans. Rev Iberoam Micol 18: 163-170.
55. Lin CH, Kabrawala S, Fox EP, Nobile CJ, Johnson AD, et al. (2013) Genetic Control of Conventional and Pheromone-Stimulated Biofilm Formation in Candida albicans. PLoS Pathog 9: e1003305.
56. Tsai PW, Chen YT, Yang CY, Chen HF, Tan TS, et al. (2014) The role of Mss11 in Candida albicans biofilm formation. Mol Genet Genomics.
57. de Souza RD, Mores AU, Cavalca L, Rosa RT, Samaranayake LP, et al. (2009) Cell surface hydrophobicity of Candida albicans isolated from elder patients undergoing denture-related candidosis. Gerodontology 26: 157-161.
58. Sandini S, Stringaro A, Arancia S, Colone M, Mondello F, et al. (2011) The MP65 gene is required for cell wall integrity, adherence to epithelial cells and biofilm formation in Candida albicans. BMC Microbiol 11: 106.
59. Rodriguez-Tudelaa JL, Arendrupb MC, Barchiesic F, Billed J, Chryssanthoue E, et al. (2008) EUCAST definitive document EDef 7.1: method for the determination of broth dilution MICs of antifungal agents for fermentative yeasts. Clin Microbiol Infect 14: 398-405.
60. Francois JM (2006) A simple method for quantitative determination of polysaccharides in fungal cell walls. Nat Protoc 1: 2995-3000.
61. Plaine A, Walker L, Da Costa G, Mora-Montes HM, McKinnon A, et al. (2008) Functional analysis of Candida albicans GPI-anchored proteins: roles in cell wall integrity and caspofungin sensitivity. Fungal Genet Biol 45: 1404-1414.
62. Gillum AM, Tsay EY, Kirsch DR (1984) Isolation of the Candida albicans gene for orotidine-5'-phosphate decarboxylase by complementation of S. cerevisiae ura3 and E. coli pyrF mutations. Mol Gen Genet 198: 179-182.
63. Marion RM, Regev A, Segal E, Barash Y, Koller D, et al. (2004) Sfp1 is a stress- and nutrient-sensitive regulator of ribosomal protein gene expression. Proc Natl Acad Sci U S A 101: 14315-14322.
64. Jorgensen P, Nishikawa JL, Breitkreutz BJ, Tyers M (2002) Systematic identification of pathways that couple cell growth and division in yeast. Science 297: 395-400.
65. Jorgensen P, Rupes I, Sharom JR, Schneper L, Broach JR, et al. (2004) A dynamic transcriptional network communicates growth potential to ribosome synthesis and critical cell size. Genes Dev 18: 2491-2505.
66. Lempiainen H, Uotila A, Urban J, Dohnal I, Ammerer G, et al. (2009) Sfp1 interaction with TORC1 and Mrs6 reveals feedback regulation on TOR signaling. Mol Cell 33: 704-716.
67. Fingerman I, Nagaraj V, Norris D, Vershon AK (2003) Sfp1 plays a key role in yeast ribosome biogenesis. Eukaryot Cell 2: 1061-1068.
68. Kucharikova S, Tournu H, Lagrou K, Van Dijck P, Bujdakova H (2011) Detailed comparison of Candida albicans and Candida glabrata biofilms under different conditions and their susceptibility to caspofungin and anidulafungin. J Med Microbiol 60: 1261-1269.
69. Nobile CJ, Schneider HA, Nett JE, Sheppard DC, Filler SG, et al. (2008) Complementary adhesin function in C. albicans biofilm formation. Curr Biol 18: 1017-1024.
70. Chen YT, Lin CY, Tsai PW, Yang CY, Hsieh WP, et al. (2012) Rhb1 regulates the expression of secreted aspartic protease 2 through the TOR signaling pathway in Candida albicans. Eukaryot Cell 11: 168-182.
71. Argimon S, Wishart JA, Leng R, Macaskill S, Mavor A, et al. (2007) Developmental regulation of an adhesin gene during cellular morphogenesis in the fungal pathogen Candida albicans. Eukaryot Cell 6: 682-692.
72. Nobile CJ, Mitchell AP (2005) Regulation of cell-surface genes and biofilm formation by the C. albicans transcription factor Bcr1p. Curr Biol 15: 1150-1155.
73. Ramage G, VandeWalle K, Lopez-Ribot JL, Wickes BL (2002) The filamentation pathway controlled by the Efg1 regulator protein is required for normal biofilm formation and development in Candida albicans. FEMS Microbiol Lett 214: 95-100.
74. Stichternoth C, Ernst JF (2009) Hypoxic adaptation by Efg1 regulates biofilm formation by Candida albicans. Appl Environ Microbiol 75: 3663-3672.
75. Nobile CJ, Andes DR, Nett JE, Smith FJ, Yue F, et al. (2006) Critical role of Bcr1-dependent adhesins in C. albicans biofilm formation in vitro and in vivo. PLoS Pathog 2: e63.
76. Silva-Dias A, Miranda IM, Branco J, Monteiro-Soares M, Pina-Vaz C, et al. (2015) Adhesion, biofilm formation, cell surface hydrophobicity, and antifungal planktonic susceptibility: relationship among Candida spp. Front Microbiol 6: 205.
77. Bates S, MacCallum DM, Bertram G, Munro CA, Hughes HB, et al. (2005) Candida albicans Pmr1p, a secretory pathway P-type Ca2+/Mn2+-ATPase, is required for glycosylation and virulence. J Biol Chem 280: 23408-23415.
78. Wheeler RT, Kombe D, Agarwala SD, Fink GR (2008) Dynamic, morphotype-specific Candida albicans beta-glucan exposure during infection and drug treatment. PLoS Pathog 4: e1000227.
79. Rueda C, Cuenca-Estrella M, Zaragoza O (2014) Paradoxical growth of Candida albicans in the presence of caspofungin is associated with multiple cell wall rearrangements and decreased virulence. Antimicrob Agents Chemother 58: 1071-1083.
80. Bachmann SP, VandeWalle K, Ramage G, Patterson TF, Wickes BL, et al. (2002) In vitro activity of caspofungin against Candida albicans biofilms. Antimicrob Agents Chemother 46: 3591-3596.
81. Chen HF, Lan CY (2015) Role of SFP1 in the Regulation of Candida albicans Biofilm Formation. PLoS One 10: e0129903.
82. Tumbarello M, Posteraro B, Trecarichi EM, Fiori B, Rossi M, et al. (2007) Biofilm production by Candida species and inadequate antifungal therapy as predictors of mortality for patients with candidemia. J Clin Microbiol 45: 1843-1850.
83. Daniels KJ, Park YN, Srikantha T, Pujol C, Soll DR (2013) Impact of environmental conditions on the form and function of Candida albicans biofilms. Eukaryot Cell 12: 1389-1402.
84. Baillie GS, Douglas LJ (1999) Role of dimorphism in the development of Candida albicans biofilms. J Med Microbiol 48: 671-679.
85. Green CB, Zhao X, Hoyer LL (2005) Use of green fluorescent protein and reverse transcription-PCR to monitor Candida albicans agglutinin-like sequence gene expression in a murine model of disseminated candidiasis. Infect Immun 73: 1852-1855.
86. Nobile CJ, Nett JE, Andes DR, Mitchell AP (2006) Function of Candida albicans adhesin Hwp1 in biofilm formation. Eukaryot Cell 5: 1604-1610.
87. Staab JF, Ferrer CA, Sundstrom P (1996) Developmental expression of a tandemly repeated, proline-and glutamine-rich amino acid motif on hyphal surfaces on Candida albicans. J Biol Chem 271: 6298-6305.
88. Fan Y, He H, Dong Y, Pan H (2013) Hyphae-specific genes HGC1, ALS3, HWP1, and ECE1 and relevant signaling pathways in Candida albicans. Mycopathologia 176: 329-335.
89. Fu Y, Ibrahim AS, Sheppard DC, Chen YC, French SW, et al. (2002) Candida albicans Als1p: an adhesin that is a downstream effector of the EFG1 filamentation pathway. Mol Microbiol 44: 61-72.
90. Stoldt VR, Sonneborn A, Leuker CE, Ernst JF (1997) Efg1p, an essential regulator of morphogenesis of the human pathogen Candida albicans, is a member of a conserved class of bHLH proteins regulating morphogenetic processes in fungi. EMBO J 16: 1982-1991.
91. Ruiz-Herrera J, Elorza MV, Valentin E, Sentandreu R (2006) Molecular organization of the cell wall of Candida albicans and its relation to pathogenicity. FEMS Yeast Res 6: 14-29.
92. Dranginis AM, Rauceo JM, Coronado JE, Lipke PN (2007) A biochemical guide to yeast adhesins: glycoproteins for social and antisocial occasions. Microbiol Mol Biol Rev 71: 282-294.
93. Douglas CM, D'Ippolito JA, Shei GJ, Meinz M, Onishi J, et al. (1997) Identification of the FKS1 gene of Candida albicans as the essential target of 1,3-beta-D-glucan synthase inhibitors. Antimicrob Agents Chemother 41: 2471-2479.
94. Letscher-Bru V, Herbrecht R (2003) Caspofungin: the first representative of a new antifungal class. J Antimicrob Chemother 51: 513-521.
95. Rauceo JM, Blankenship JR, Fanning S, Hamaker JJ, Deneault JS, et al. (2008) Regulation of the Candida albicans cell wall damage response by transcription factor Sko1 and PAS kinase Psk1. Mol Biol Cell 19: 2741-2751.
96. Delgado-Silva Y, Vaz C, Carvalho-Pereira J, Carneiro C, Nogueira E, et al. (2014) Participation of Candida albicans transcription factor RLM1 in cell wall biogenesis and virulence. PLoS One 9: e86270.
97. Robbins N, Uppuluri P, Nett J, Rajendran R, Ramage G, et al. (2011) Hsp90 governs dispersion and drug resistance of fungal biofilms. PLoS Pathog 7: e1002257.
98. 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: 5146-5148.
99. Karkhanis YD, Schmatz DM (1998) Novel enzyme-linked immunoassay to determine nanogram levels of pneumocandins in human plasma. J Clin Microbiol 36: 1414-1418.
100. Hawser SP, Douglas LJ (1994) Biofilm formation by Candida species on the surface of catheter materials in vitro. Infect Immun 62: 915-921.
101. Nett JE, Sanchez H, Cain MT, Andes DR (2010) Genetic basis of Candida biofilm resistance due to drug-sequestering matrix glucan. J Infect Dis 202: 171-175.
102. Vediyappan G, Rossignol T, d'Enfert C (2010) Interaction of Candida albicans biofilms with antifungals: transcriptional response and binding of antifungals to beta-glucans. Antimicrob Agents Chemother 54: 2096-2111.
103. Lavoie H, Hogues H, Mallick J, Sellam A, Nantel A, et al. (2010) Evolutionary tinkering with conserved components of a transcriptional regulatory network. PLoS Biol 8: e1000329.
104. Hao B, Cheng S, Clancy CJ, Nguyen MH (2013) Caspofungin kills Candida albicans by causing both cellular apoptosis and necrosis. Antimicrob Agents Chemother 57: 326-332.