Chapter 25 : Multidrug Resistance Transcriptional Regulatory Networks in

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Ebook: Choose a downloadable PDF or ePub file. Chapter is a downloadable PDF file. File must be downloaded within 48 hours of purchase

Buy this Chapter
Digital (?) $15.00

Preview this chapter:
Zoom in

Multidrug Resistance Transcriptional Regulatory Networks in , Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555817176/9781555815394_Chap25-1.gif /docserver/preview/fulltext/10.1128/9781555817176/9781555815394_Chap25-2.gif


species are an important cause of both mucosal and invasive opportunistic infections among immuno-compromised patient populations, such as cancer patients receiving cytotoxic chemotherapy, solid-organ and bone marrow transplant patients receiving immunosuppressant therapy, and patients infected with human immunodeficiency virus (HIV) and suffering from AIDS. Moreover, recent reports have highlighted a paradoxical OPC infection rate of 30% in HIV-infected individuals who have shown improvements in CD4 counts and have been classified as ''immune reconstituted''. This chapter focuses on the transcriptional regulation of azole antifungal resistance as well as transcriptional regulators that influence azole susceptibility in species. Much of our understanding of azole antifungal resistance in species has been greatly facilitated by the study of the pleiotropic drug resistance phenotype in , which is largely driven by ATP-binding cassette (ABC) transporters such as Pdr5p. In a study to generate a more global assessment of Ndt80p, it was found that Ndt80p was bound to the promoters of many genes previously identified as being associated with azole resistance, including the ABC transporter genes , , and ; the MFS transporter genes , , , and ; the flippase genes and ; and other azole resistance-associated genes, , , and .

Citation: Rogers P, Barker K. 2012. Multidrug Resistance Transcriptional Regulatory Networks in , p 403-416. In Calderone R, Clancy C (ed), and Candidiasis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817176.ch25
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of FIGURE 1

Promoter regions containing known response elements of the , and genes. Each binding region is shaded or patterned according to the type of response element, the 5‵ boundary of the ORFs is indicated by the bent arrow, and the ORFs are indicated by the shaded arrow. (A) The gene promoter contains MSEs putatively bound by Ndt80p ( ), SREs shown to be progesterone responsive (SRE1) or progesterone- and estradiol-responsive (SRE2) ( ), and a DRE putatively bound by Tac1p ( ). (B) The gene promoter contains an HRE and BRE ( ), which both overlap with constitutive activation regions 2 and 3, respectively ( ). An additional region (region 1) was also identified by Hiller et al. ( ). The MDRE, putatively bound by Mcm1p ( ), is contained within the boundaries of the BRE. The -butyl-hydroperoxide (T-BHP)-responsive and benomyl (BEN)-responsive elements ( ) are found within regions 2 and 1, respectively. (C) The gene promoter contains two SREs, presumably bound by Upc2p ( ), and an azole response element (ARE) ( ). doi:10.1128/9781555817176.ch25.f1

Citation: Rogers P, Barker K. 2012. Multidrug Resistance Transcriptional Regulatory Networks in , p 403-416. In Calderone R, Clancy C (ed), and Candidiasis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817176.ch25
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 2

Representation of gain-of-function mutations identified to date in Tac1p, Mrr1p, Upc2p, and CgPdr1p. Each protein is displayed from N to C terminus (left to right). The shaded and patterned boxes correspond to functional motifs defined as follows: ZnCys zinc finger DNA-binding domain in medium gray boxes, activation domain of Tac1p ( ) and of CgPdr1p ( ) in black boxes, putative NLS of Upc2p and of CgPdr1p in horizontally hatched boxes, and xenobiotic binding domain of CgPdr1p ( ) in light gray boxes. Only gain-of-function mutations that have been experimentally verified are shown. The Tac1p mutations were originally described by Coste et al. ( ) and Znaidi et al. ( ), the Mrr1p mutations were originally described by Morschhäuser et al. ( ) and Dunkel et al. ( ), the Upc2p mutations were originally described by Dunkel et al. ( ) and Heilmann et al. ( ), and the Pdr1p mutations were originally described by Ferrari et al. ( ), Torelli et al. ( ), Tsai et al. ( ), Vermitsky and Edlind ( ), and K. E. Caudle et al. (unpublished data). doi:10.1128/9781555817176.ch25.f2

Citation: Rogers P, Barker K. 2012. Multidrug Resistance Transcriptional Regulatory Networks in , p 403-416. In Calderone R, Clancy C (ed), and Candidiasis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817176.ch25
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Alarco, A. M.,, I. Balan,, D. Talibi,, N. Mainville, and, M. Raymond. 1997. AP1-mediated multidrug resistance in Saccharomyces cerevisiae requires FLR1 encoding a transporter of the major facilitator superfamily. J. Biol. Chem. 272: 1930419313.
2. Alarco, A. M., and, M. Raymond. 1999. The bZip transcription factor Cap1p is involved in multidrug resistance and oxidative stress response in Candida albicans. J. Bacteriol. 181: 700708.
3. Balan, I.,, A. M. Alarco, and, M. Raymond. 1997. The Candida albicans CDR3 gene codes for an opaque-phase ABC transporter. J. Bacteriol. 179: 72107218.
4. Barchiesi, F.,, D. Calabrese,, D. Sanglard,, L. Falconi Di Francesco,, F. Caselli,, D. Giannini,, A. Giacometti,, S. Gavaudan, and, G. Scalise. 2000. Experimental induction of fluconazole resistance in Candida tropicalis ATCC 750. Antimicrob. Agents Chemother. 44: 15781584.
5. Bennett, J. E.,, K. Izumikawa, and, K. A. Marr. 2004. Mechanism of increased fluconazole resistance in Candida glabrata during prophylaxis. Antimicrob. Agents Chemother. 48: 17731777.
6. Ben-Yaacov, R.,, S. Knoller,, G. A. Caldwell,, J. M. Becker, and, Y. Koltin. 1994. Candida albicans gene encoding resistance to benomyl and methotrexate is a multidrug resistance gene. Antimicrob. Agents Chemother. 38: 648652.
7. Bruno, V. M.,, S. Kalachikov,, R. Subaran,, C. J. Nobile,, C. Kyratsous, and, A. P. Mitchell. 2006. Control of the C. albicans cell wall damage response by transcriptional regulator Cas5. PLoS Pathog. 2: e21.
8. Bustamante, C. I. 2005. Treatment of Candida infection: a view from the trenches! Curr. Opin. Infect. Dis. 18: 490495.
9. Calabrese, D.,, J. Bille, and, D. Sanglard. 2000. A novel multidrug efflux transporter gene of the major facilitator superfamily from Candida albicans (FLU1) conferring resistance to fluconazole. Microbiology 146: 27432754.
10. Chapeland-Leclerc, F.,, C. Hennequin,, N. Papon,, T. Noël,, A. Girard,, G. Socié,, P. Ribaud, and, C. Lacroix. 2010. Acquisition of flucytosine, azole, and caspofungin resistance in Candida glabrata bloodstream isolates serially obtained from a hematopoietic stem cell transplant recipient. Antimicrob. Agents Chemother. 54: 13601362.
11. Chen, C. G.,, Y. L. Yang,, H. I. Shih,, C. L. Su, and, H. J. Lo. 2004. CaNdt80 is involved in drug resistance in Candida albicans by regulating CDR1. Antimicrob. Agents Chemother. 48: 45054512.
12. Chen, C. G.,, Y. L. Yang,, K. Y. Tseng,, H. I. Shih,, C. H. Liou,, C. C. Lin, and, H. J. Lo. 2009. Rep1p negatively regulating MDR1 efflux pump involved in drug resistance in Candida albicans. Fungal Genet. Biol. 46: 714720.
13. Chen, K. H.,, T. Miyazaki,, H. F. Tsai, and, J. E. Bennett. 2007. The bZip transcription factor Cgap1p is involved in multidrug resistance and required for activation of multi-drug transporter gene CgFLR1 in Candida glabrata. Gene 386: 6372.
14. Reference deleted.
15. Cleary, J. D.,, G. Garcia-Effron,, S. W. Chapman, and, D. S. Perlin. 2008. Reduced Candida glabrata susceptibility secondary to an FKS1 mutation developed during candidemia treatment. Antimicrob. Agents Chemother. 52: 22632265.
16. Coste, A.,, V. Turner,, F. Ischer,, J. Morschhäuser,, A. Forche,, A. Selmecki,, J. Berman,, J. Bille, and, D. Sanglard. 2006. A mutation in Tac1p, a transcription factor regulating CDR1 and CDR2, is coupled with loss of heterozygosity at chromosome 5 to mediate antifungal resistance in Candida albicans. Genetics 172: 21392156.
17. Coste, A. T.,, M. Karababa,, F. Ischer,, J. Bille, and, D. Sanglard. 2004. TAC1, transcriptional activator of CDR genes, is a new transcription factor involved in the regulation of Candida albicans ABC transporters CDR1 and CDR2. Eukaryot. Cell 3: 16391652.
18. Reference deleted.
19. de Micheli, M.,, J. Bille,, C. Schueller, and, D. Sanglard. 2002. A common drug-responsive element mediates the upregulation of the Candida albicans ABC transporters CDR1 and CDR2, two genes involved in antifungal drug resistance. Mol. Microbiol. 43: 11971214.
20. Dizbay, M.,, I. Fidan,, A. Kalkanci,, N. Sari,, B. Yalcin,, S. Kustimur, and, D. Arman. 2010. High incidence of Candida parapsilosis candidaemia in non-neutropenic critically ill patients: epidemiology and antifungal susceptibility. Scand. J. Infect. Dis. 42: 114120.
21. Dujon, B.,, D. Sherman,, G. Fischer,, P. Durrens,, S. Casaregola,, I. Lafontaine,, J. De Montigny,, C. Marck,, C. Neuvéglise,, E. Talla,, N. Goffard,, L. Frangeul,, M. Aigle,, V. Anthouard,, A. Babour,, V. Barbe,, S. Barnay,, S. Blanchin,, J. M. Beckerich,, E. Beyne,, C. Bleykasten,, A. Boisramé,, J. Boyer,, L. Cattolico,, F. Confanioleri,, A. De Daruvar,, L. Despons,, E. Fabre,, C. Fairhead,, H. Ferry-Dumazet,, A. Groppi,, F. Hantraye,, C. Hennequin,, N. Jauniaux,, P. Joyet,, R. Kachouri,, A. Kerrest,, R. Koszul,, M. Lemaire,, I. Lesur,, L. Ma,, H. Muller,, J. M. Nicaud,, M. Nikolski,, S. Oztas,, O. Ozier-Kalogeropoulos,, S. Pellenz,, S. Potier,, G. F. Richard,, M. L. Straub,, A. Suleau,, D. Swennen,, F. Tekaia,, M. Wésolowski-Louvel,, E. West-hof,, B. Wirth,, M. Zeniou-Meyer,, I. Zivanovic,, M. Bolotin-Fukuhara,, A. Thierry,, C. Bouchier,, B. Caudron,, C. Scarpelli,, C. Gaillardin,, J. Weissenbach,, P. Wincker, and, J. L. Souciet. 2004. Genome evolution in yeasts. Nature 430: 3544.
22. Dunkel, N.,, J. Blass,, P. D. Rogers, and, J. Morschhäuser. 2008. Mutations in the multi-drug resistance regulator MRR1, followed by loss of heterozygosity, are the main cause of MDR1 overexpression in fluconazole-resistant Candida albicans strains. Mol. Microbiol. 69: 827840.
23. Dunkel, N.,, T. T. Liu,, K. S. Barker,, R. Homayouni,, J. Morschhäuser, and, P. D. Rogers. 2008. A gain-of-function mutation in the transcription factor Upc2p causes upregulation of ergosterol biosynthesis genes and increased fluconazole resistance in a clinical Candida albicans isolate. Eukaryot. Cell 7: 11801190.
24. Ferrari, S.,, F. Ischer,, D. Calabrese,, B. Posteraro,, M. Sanguinetti,, G. Fadda,, B. Rohde,, C. Bauser,, O. Bader, and, D. Sanglard. 2009. Gain of function mutations in CgPDR1 of Candida glabrata not only mediate antifungal resistance but also enhance virulence. PLoS Pathog. 5: e1000268.
25. Fling, M. E.,, J. Kopf,, A. Tamarkin,, J. A. Gorman,, H. A. Smith, and, Y. Koltin. 1991. Analysis of a Candida albicans gene that encodes a novel mechanism for resistance to benomyl and methotrexate. Mol. Gen. Genet. 227: 318329.
26. Franz, R.,, S. L. Kelly,, D. C. Lamb,, D. E. Kelly,, M. Ruhnke, and, J. Morschhäuser. 1998. Multiple molecular mechanisms contribute to a stepwise development of fluconazole resistance in clinical Candida albicans strains. Antimicrob. Agents Chemother. 42: 30653072.
27. Franz, R.,, S. Michel, and, J. Morschhäuser. 1998. A fourth gene from the Candida albicans CDR family of ABC transporters. Gene 220: 9198.
28. Franz, R.,, M. Ruhnke, and, J. Morschhäuser. 1999. Molecular aspects of fluconazole resistance development in Candida albicans. Mycoses 42: 453458.
29. Gaitan Cepeda, L. A.,, A. Ceballos Salobreña,, K. López Ortega,, N. Arzate Mora, and, Y. Jiménez Soriano. 2008. Oral lesions and immune reconstitution syndrome in HIV+/ AIDS patients receiving highly active antiretroviral therapy. Epidemiological evidence. Med. Oral Patol. Oral Cir. Bucal. 13: E85E93.
30. Gallis, H. A.,, R. H. Drew, and, W. W. Pickard. 1990. Amphotericin B: 30 years of clinical experience. Rev. Infect. Dis. 12: 308329.
31. Garcia-Effron, G.,, D. P. Kontoyiannis,, R. E. Lewis, and, D. S. Perlin. 2008. Caspofungin-resistant Candida tropicalis strains causing breakthrough fungemia in patients at high risk for hematologic malignancies. Antimicrob. Agents Chemother. 52: 41814183.
32. Ghannoum, M. A., and, L. B. Rice. 1999. Antifungal agents: mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance. Clin. Microbiol. Rev. 12: 501517.
33. Harry, J. B.,, B. G. Oliver,, J. L. Song,, P. M. Silver,, J. T. Little,, J. Choiniere, and, T. C. White. 2005. Drug-induced regulation of the MDR1 promoter in Candida albicans. Antimicrob. Agents Chemother. 49: 27852792.
34. Heilmann, C. J.,, S. Schneider,, K. S. Barker,, P. D. Rogers, and, J. Morschhäuser. 2010. An A643T mutation in the transcription factor Upc2p causes constitutive ERG11 upregulation and increased fluconazole resistance in Candida albicans. Antimicrob. Agents Chemother. 54: 353359.
35. Hernáez, M. L.,, C. Gil,, J. Pla, and, C. Nombela. 1998. Induced expression of the Candida albicans multidrug resistance gene CDR1 in response to fluconazole and other antifungals. Yeast 14: 517526.
36. Hiller, D.,, D. Sanglard, and, J. Morschhäuser. 2006. Overexpression of the MDR1 gene is sufficient to confer increased resistance to toxic compounds in Candida albicans. Antimicrob. Agents Chemother. 50: 13651371.
37. Hiller, D.,, S. Stahl, and, J. Morschhäuser. 2006. Multiple cis-acting sequences mediate upregulation of the MDR1 efflux pump in a fluconazole-resistant clinical Candida albicans isolate. Antimicrob. Agents Chemother. 50: 23002308.
38. Izumikawa, K.,, H. Kakeya,, H. F. Tsai,, B. Grimberg, and, J. E. Bennett. 2003. Function of Candida glabrata ABC transporter gene, PDH1. Yeast 20: 249261.
39. Karababa, M.,, E. Valentino,, G. Pardini,, A. T. Coste,, J. Bille, and, D. Sanglard. 2006. CRZ1, a target of the calcineurin pathway in Candida albicans. Mol. Microbiol. 59: 14291451.
40. Karnani, N.,, N. A. Gaur,, S. Jha,, N. Puri,, S. Krishna-murthy,, S. K. Goswami,, G. Mukhopadhyay, and, R. Prasad. 2004. SRE1 and SRE2 are two specific steroid-responsive modules of Candida drug resistance gene 1 (CDR1) promoter. Yeast 21: 219239.
41. Katiyar, S. K., and, T. D. Edlind. 2001. Identification and expression of multidrug resistance-related ABC transporter genes in Candida krusei. Med. Mycol. 39: 109116.
42. Kelly, S. L.,, A. Arnoldi, and, D. E. Kelly. 1993. Molecular genetic analysis of azole antifungal mode of action. Biochem. Soc. Trans. 21: 10341038.
43. Kelly, S. L.,, D. C. Lamb,, D. E. Kelly,, J. Loeffler, and, H. Einsele. 1996. Resistance to fluconazole and amphotericin in Candida albicans from AIDS patients. Lancet 348: 15231524.
44. Kelly, S. L.,, D. C. Lamb,, D. E. Kelly,, N. J. Manning,, J. Loeffler,, H. Hebart,, U. Schumacher, and, H. Einsele. 1997. Resistance to fluconazole and cross-resistance to amphotericin B in Candida albicans from AIDS patients caused by defective sterol delta5,6-desaturation. FEBS Lett. 400: 8082.
45. Kofteridis, D. P.,, R. E. Lewis, and, D. P. Kontoyiannis. 2010. Caspofungin-non-susceptible Candida isolates in cancer patients. J. Antimicrob. Chemother. 65: 293295.
46. Reference deleted.
47. Kontoyiannis, D. P., and, R. E. Lewis. 2002. Antifungal drug resistance of pathogenic fungi. Lancet 359: 11351144.
48. Krishnamurthy, S.,, V. Gupta,, R. Prasad,, S. L. Panwar, and, R. Prasad. 1998. Expression of CDR1, a multidrug resistance gene of Candida albicans: transcriptional activation by heat shock, drugs and human steroid hormones. FEMS Microbiol. Lett. 160: 191197.
49. Kudo, M.,, M. Ohi,, Y. Aoyama,, Y. Nitahara,, S. K. Chung, and, Y. Yoshida. 2005. Effects of Y132H and F145L substitutions on the activity, azole resistance and spectral properties of Candida albicans sterol 14-demethylase P450 (CYP51): a live example showing the selection of altered P450 through interaction with environmental compounds. J. Biochem. 137: 625632.
50. Lavoie, H.,, A. Sellam,, C. Askew,, A. Nantel, and, M. Whiteway. 2008. A toolbox for epitope-tagging and genome-wide location analysis in Candida albicans. BMC Genomics 9: 578.
51. Lee, M. K.,, L. E. Williams,, D. W. Warnock, and, B. A. Arthington-Skaggs. 2004. Drug resistance genes and trailing growth in Candida albicans isolates. J. Antimicrob. Chemother. 53: 217224.
52. Liu, T. T.,, R. E. Lee,, K. S. Barker,, R. E. Lee,, L. Wei,, R. Homayouni, and, P. D. Rogers. 2005. Genome-wide expression profiling of the response to azole, polyene, echinocandin, and pyrimidine antifungal agents in Candida albicans. Antimicrob. Agents Chemother. 49: 22262236.
53. Liu, T. T.,, S. Znaidi,, K. S. Barker,, L. Xu,, R. Homayouni,, S. Saidane,, J. Morschhäuser,, A. Nantel,, M. Raymond, and, P. D. Rogers. 2007. Genome-wide expression and location analyses of the Candida albicans Tac1p regulon. Eukaryot. Cell 6: 21222138.
54. Lopez-Ribot, J. L.,, R. K. McAtee,, L. N. Lee,, W. R. Kirkpatrick,, T. C. White,, D. Sanglard, and, T. F. Patterson. 1998. Distinct patterns of gene expression associated with development of fluconazole resistance in serial Candida albicans isolates from human immunodeficiency virus-infected patients with oropharyngeal candidiasis. Antimicrob. Agents Chemother. 42: 29322937.
55. Lyman, C. A., and, T. J. Walsh. 1992. Systemically administered antifungal agents. A review of their clinical pharmacology and therapeutic applications. Drugs 44: 935.
56. Lyons, C. N., and, T. C. White. 2000. Transcriptional analyses of antifungal drug resistance in Candida albicans. Antimicrob. Agents Chemother. 44: 22962303.
57. MacPherson, S.,, B. Akache,, S. Weber,, X. De Deken,, M. Raymond, and, B. Turcotte. 2005. Candida albicans zinc cluster protein Upc2p confers resistance to antifungal drugs and is an activator of ergosterol biosynthetic genes. Antimicrob. Agents Chemother. 49: 17451752.
58. Martins, M. D.,, M. Lozano-Chiu, and, J. H. Rex. 1998. Declining rates of oropharyngeal candidiasis and carriage of Candida albicans associated with trends toward reduced rates of carriage of fluconazole-resistant C. albicans in human immunodeficiency virus-infected patients. Clin. Infect. Dis. 27: 12911294.
59. Miyazaki, H.,, Y. Miyazaki,, A. Geber,, T. Parkinson,, C. Hitchcock,, D. J. Falconer,, D. J. Ward,, K. Marsden, and, J. E. Bennett. 1998. Fluconazole resistance associated with drug efflux and increased transcription of a drug transporter gene, PDH1, in Candida glabrata. Antimicrob. Agents Chemother. 42: 16951701.
60. Miyazaki, T.,, S. Yamauchi,, T. Inamine,, Y. Nagayoshi,, T. Saijo,, K. Izumikawa,, M. Seki,, H. Kakeya,, Y. Yamamoto,, K. Yanagihara,, Y. Miyazaki, and, S. Kohno. 2010. Roles of calcineurin and Crz1 in antifungal susceptibility and virulence of Candida glabrata. Antimicrob. Agents Chemother. 54: 16391643.
61. Moran, G.,, D. Sullivan,, J. Morschhäuser, and, D. Coleman. 2002. The Candida dubliniensis CdCDR1 gene is not essential for fluconazole resistance. Antimicrob. Agents Chemother. 46: 28292841.
62. Morschhäuser, J. 2002. The genetic basis of fluconazole resistance development in Candida albicans. Biochim. Biophys. Acta 1587: 240248.
63. Morschhäuser, J.,, K. S. Barker,, T. T. Liu,, J. Blaß-Warmuth,, R. Homayouni, and, P. D. Rogers. 2007. The transcription factor Mrr1p controls expression of the MDR1 efflux pump and mediates multidrug resistance in Candida albicans. PLoS Pathog. 3: e164.
64. Moye-Rowley, W. S. 2003. Regulation of the transcriptional response to oxidative stress in fungi: similarities and differences. Eukaryot. Cell 2: 381389.
65. Niimi, M.,, K. Niimi,, Y. Takano,, A. R. Holmes,, F. J. Fischer,, Y. Uehara, and, R. D. Cannon. 2004. Regulated overexpression of CDR1 in Candida albicans confers multi-drug resistance. J. Antimicrob. Chemother. 54: 9991006.
66. Niimi, K.,, K. Maki,, F. Ikeda,, A. R. Holmes,, E. Lamping,, M. Niimi,, B. C. Monk, and, R. D. Cannon. 2006. Over-expression of Candida albicans CDR1, CDR2, or MDR1 does not produce significant changes in echinocandin susceptibility. Antimicrob. Agents Chemother. 50: 11481155.
67. Nolte, F. S.,, T. Parkinson,, D. J. Falconer,, S. Dix,, J. Williams,, C. Gilmore,, R. Geller, and, J. R. Wingard. 1997. Isolation and characterization of fluconazole- and amphotericin B-resistant Candida albicans from blood of two patients with leukemia. Antimicrob. Agents Chemother. 41: 196199.
68. Nourani, A.,, D. Papajova,, A. Delahodde,, C. Jacq, and, J. Subik. 1997. Clustered amino acid substitutions in the yeast transcription regulator Pdr3p increase pleiotropic drug resistance and identify a new central regulatory domain. Mol. Gen. Genet. 256: 397405.
69. Oliver, B. G.,, J. L. Song,, J. H. Choiniere, and, T. C. White. 2007. cis-Acting elements within the Candida albicans ERG11 promoter mediate the azole response through transcription factor Upc2p. Eukaryot. Cell 6: 22312239.
70. Onyewu, C.,, F. L. Wormley, Jr.,, J. R. Perfect, and, J. Heitman. 2004. The calcineurin target, Crz1, functions in azole tolerance but is not required for virulence of Candida albicans. Infect Immun. 72: 73307333.
71. Pappas, P. G.,, C. A. Kauffman,, D. Andes,, D. K. Benjamin, Jr.,, T. F. Calandra,, J. E. Edwards, Jr.,, S. G. Filler,, J. F. Fisher,, B. J. Kullberg,, L. Ostrosky-Zeichner,, A. C. Reboli,, J. H. Rex,, T. J. Walsh, and, J. D. Sobel. 2009. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin. Infect. Dis. 48: 503535.
72. Perea, S.,, J. L. Lopez-Ribot,, W. R. Kirkpatrick,, R. K. McAtee,, R. A. Santillan,, M. Martinez,, D. Calabrese,, D. Sanglard, and, T. F. Patterson. 2001. Prevalence of molecular mechanisms of resistance to azole antifungal agents in Candida albicans strains displaying high-level fluconazole resistance isolated from human immunodeficiency virus-infected patients. Antimicrob. Agents Chemother. 45: 26762684.
73. Perlin, D. S. 2009. Antifungal drug resistance: do molecular methods provide a way forward? Curr. Opin. Infect. Dis. 22: 568573.
74. Pfaller, M. A.,, D. J. Diekema,, D. L. Gibbs,, V. A. Newell,, D. Ellis,, V. Tullio,, A. Rodloff,, W. Fu,, T. A. Ling, andthe Global Antifungal Surveillance Group. 2010. Results from the ARTEMIS DISK Global Antifungal Surveillance Study, 1997 to 2007: a 10.5-year analysis of susceptibilities of Candida species to fluconazole and voriconazole as determined by CLSI standardized disk diffusion. J. Clin. Microbiol. 48: 13661377.
75. Prasad, R.,, P. De Wergifosse,, A. Goffeau, and, E. Balzi. 1995. Molecular cloning and characterization of a novel gene of Candida albicans, CDR1, conferring multiple resistance to drugs and antifungals. Curr. Genet. 27: 320329.
76. Reference deleted.
77. Raymond, M.,, D. Dignard,, A. M. Alarco,, K. L. Clark,, S. Weber,, M. Whiteway,, E. Leberer, and, D. Y. Thomas. 2000. Molecular cloning of the CRM1 gene from Candida albicans. Yeast 16: 531538.
78. Riggle, P. J., and, C. A. Kumamoto. 2006. Transcriptional regulation of MDR1, encoding a drug efflux determinant, in fluconazole-resistant Candida albicans strains through an Mcm1p binding site. Eukaryot. Cell 5: 19571968.
79. Rogers, P. D., and, K. S. Barker. 2003. Genome-wide expression profile analysis reveals coordinately regulated genes associated with stepwise acquisition of azole resistance in Candida albicans clinical isolates. Antimicrob. Agents Chemother. 47: 12201227.
80. Rognon, B.,, Z. Kozovska,, A.T. Coste,, G. Pardini, and, D. Sanglard. 2006. Identification of promoter elements responsible for the regulation of MDR1 from Candida albicans, a major facilitator transporter involved in azole resistance. Microbiology 152: 37013722.
81. Ruhnke, M.,, A. Eigler,, I. Tennagen,, B. Geiseler,, E. Engelmann, and, M. Trautmann. 1994. Emergence of fluconazole-resistant strains of Candida albicans in patients with recurrent oropharyngeal candidosis and human immunodeficiency virus infection. J. Clin. Microbiol. 32: 20922098.
82. Saidane, S.,, S. Weber,, X. De Deken,, G. St.-Germain, and, M. Raymond. 2006. PDR16-mediated azole resistance in Candida albicans. Mol. Microbiol. 60: 15461562.
83. Sanglard, D.,, K. Kuchler,, F. Ischer,, J. L. Pagani,, M. Monod, and, J. Bille. 1995. Mechanisms of resistance to azole antifungal agents in Candida albicans isolates from AIDS patients involve specific multidrug transporters. Antimicrob. Agents Chemother. 39: 23782386.
84. Sanglard, D.,, F. Ischer,, M. Monod, and, J. Bille. 1996. Susceptibilities of Candida albicans multidrug transporter mutants to various antifungal agents and other metabolic inhibitors. Antimicrob. Agents Chemother. 40: 23002305.
85. Sanglard, D.,, F. Ischer,, M. Monod, and, J. Bille. 1997. Cloning of Candida albicans genes conferring resistance to azole antifungal agents: characterization of CDR2, a new multidrug ABC transporter gene. Microbiology 143: 405416.
86. Sanglard, D.,, F. Ischer,, L. Koymans, and, J. Bille. 1998. Amino acid substitutions in the cytochrome P-450 lanosterol 14alpha-demethylase (CYP51A1) from azole-resistant Candida albicans clinical isolates contribute to resistance to azole antifungal agents. Antimicrob. Agents Chemother. 42: 241253.
87. Sanglard, D.,, F. Ischer,, D. Calabrese,, P. A. Majcherczyk, and, J. Bille. 1999. The ATP binding cassette transporter gene CgCDR1 from Candida glabrata is involved in the resistance of clinical isolates to azole antifungal agents. Anti-microb. Agents Chemother. 43: 27532765.
88. Sanglard, D.,, F. Ischer, and, J. Bille. 2001. Role of ATP-binding-cassette transporter genes in high-frequency acquisition of resistance to azole antifungals in Candida glabrata. Antimicrob. Agents Chemother. 45: 11741183.
89. Sanglard, D. 2002. Resistance of human fungal pathogens to antifungal drugs. Curr. Opin. Microbiol. 5: 379385.
90. Sanglard, D.,, F. Ischer,, O. Marchetti,, J. Entenza, and, J. Bille. 2003. Calcineurin A of Candida albicans: involvement in antifungal tolerance, cell morphogenesis and virulence. Mol. Microbiol. 48: 959976.
91. Sanglard, D.,, A. Coste, and, S. Ferrari. 2009. Antifungal drug resistance mechanisms in fungal pathogens from the perspective of transcriptional gene regulation. FEMS Yeast Res. 9: 10291050.
92. Sanguinetti, M.,, B. Posteraro,, B. Fiori,, S. Ranno,, R. Torelli, and, G. Fadda. 2005. Mechanisms of azole resistance in clinical isolates of Candida glabrata collected during a hospital survey of antifungal resistance. Antimicrob. Agents Chemother. 49: 668679.
93. Schubert, S.,, P. D. Rogers, and, J. Morschhäuser. 2008. Gain-of-function mutations in the transcription factor MRR1 are responsible for overexpression of the MDR1 efflux pump in fluconazole-resistant Candida dubliniensis strains. Antimicrob. Agents Chemother. 52: 42744280.
94. Sellam, A.,, F. Tebbji, and, A. Nantel. 2009. Role of Ndt80p in sterol metabolism regulation and azole resistance in Candida albicans. Eukaryot. Cell 8: 11741183.
95. Sellam, A.,, C. Askew,, E. Epp,, H. Lavoie,, M. Whiteway, and, A. Nantel. 2009. Genome-wide mapping of the co-activator Ada2p yields insight into the functional roles of SAGA/ADA complex in Candida albicans. Mol. Biol. Cell 20: 23892400.
96. Selmecki, A.,, A. Forche, and, J. Berman. 2006. Aneuploidy and isochromosome formation in drug-resistant Candida albicans. Science 313: 367370.
97. Reference deleted.
98. Shukla, S.,, P. Saini,, Smriti, S. Jha,, S. V. Ambudkar, and, R. Prasad. 2003. Functional characterization of Candida albicans ABC transporter Cdr1. Eukaryot. Cell 2: 13611375.
99. Shukla, S.,, V. Rai,, D. Banerjee, and, R. Prasad. 2006. Characterization of Cdr1p, a major multidrug efflux protein of Candida albicans: purified protein is amenable to intrinsic fluorescence analysis. Biochemistry 45: 24252435.
100. Silver, P. M.,, B. G. Oliver, and, T. C. White. 2004. Role of Candida albicans transcription factor Upc2p in drug resistance and sterol metabolism. Eukaryot. Cell 3: 13911397.
101. Slain, D. 1999. Lipid-based amphotericin B for the treatment of fungal infections. Pharmacotherapy 19: 306323.
102. Smith, W. L., and, T. D. Edlind. 2002. Histone deacetylase inhibitors enhance Candida albicans sensitivity to azoles and related antifungals: correlation with reduction in CDR and ERG upregulation. Antimicrob. Agents Chemother. 46: 35323539.
103. Sucher, A. J.,, E. B. Chahine,, H. E. Balcer. 2009. Echinocandins: the newest class of antifungals. Ann. Pharmacother. 43: 16471657.
104. Talibi, D., and, M. Raymond. 1999. Isolation of a putative Candida albicans transcriptional regulator involved in pleiotropic drug resistance by functional complementation of a pdr1 pdr3 mutation in Saccharomyces cerevisiae. J. Bacteriol. 181: 231240.
105. Thakur, J. K.,, H. Arthanari,, F. Yang,, S. J. Pan,, X. Fan,, J. Breger,, D. P. Frueh,, K. Gulshan,, D. K. Li,, E. Mylonakis,, K. Struhl,, W. S. Moye-Rowley,, B. P. Cormack,, G. Wagner, and, A. M. Näär. 2008. A nuclear receptor-like pathway regulating multidrug resistance in fungi. Nature 452: 604609.
106. Torelli, R.,, B. Posteraro,, S. Ferrari,, M. La Sorda,, G. Fadda,, D. Sanglard, and, M. Sanguinetti. 2008. The ATP-binding cassette transporter-encoding gene CgSNQ2 is contributing to the CgPDR1-dependent azole resistance of Candida glabrata. Mol. Microbiol. 68: 186201.
107. Traeder, C.,, S. Kowoll, and, K. Arastéh. 2008. Candida infection in HIV positive patients 1985–2007. Mycoses 51 (Suppl. 2): 5861.
108. Tsai, H. F.,, A. A. Krol,, K. E. Sarti, and, J. E. Bennett. 2006. Candida glabrata PDR1, a transcriptional regulator of a pleiotropic drug resistance network, mediates azole resistance in clinical isolates and petite mutants. Antimicrob. Agents Chemother. 50: 13841392.
109. Tsao, S.,, F. Rahkhoodaee, and, M. Raymond. 2009. Relative contributions of the Candida albicans ABC transporters Cdr1p and Cdr2p to clinical azole resistance. Antimicrob. Agents Chemother. 53: 13441352.
110. Vermitsky, J. P., and, T. D. Edlind. 2004. Azole resistance in Candida glabrata: coordinate upregulation of multidrug transporters and evidence for a Pdr1-like transcription factor. Antimicrob. Agents Chemother. 48: 37733781.
111. Vermitsky, J. P.,, K. D. Earhart,, W. L. Smith,, R. Homayouni,, T. D. Edlind, and, P. D. Rogers. 2006. Pdr1 regulates multidrug resistance in Candida glabrata: gene disruption and genome-wide expression studies. Mol. Microbiol. 61: 704722.
112. Vik, A., and, J. Rine. 2001. Upc2p and Ecm22p, dual regulators of sterol biosynthesis in Saccharomyces cerevisiae. Mol. Cell. Biol. 21: 63956405.
113. Wada, S.,, M. Niimi,, K. Niimi,, A. R. Holmes,, B. C. Monk,, R. D. Cannon, and, Y. Uehara. 2002. Candida glabrata ATP-binding cassette transporters Cdr1p and Pdh1p expressed in a Saccharomyces cerevisiae strain deficient in membrane transporters show phosphorylation-dependent pumping properties. J. Biol. Chem. 277: 4680946821.
114. Wang, J. S.,, Y. L. Yang,, C. J. Wu,, K. J. Ouyang,, K. Y. Tseng,, C. G. Chen,, H. Wang, and, H. J. Lo. 2006. The DNA-binding domain of CaNdt80p is required to activate CDR1 involved in drug resistance in Candida albicans. J. Med. Microbiol. 55: 14031411.
115. White, T. C. 1997. The presence of an R467K amino acid substitution and loss of allelic variation correlate with an azole-resistant lanosterol 14α demethylase in Candida albicans. Antimicrob. Agents Chemother. 41: 14881494.
116. White, T. C.,, K. A. Marr, and, R. A. Bowden. 1998. Clinical, cellular, and molecular factors that contribute to antifungal drug resistance. Clin. Microbiol. Rev. 11: 382402.
117. Wirsching, S.,, S. Michel,, G. Kohler, and, J. Morschhäuser. 2000. Activation of the multiple drug resistance gene MDR1 in fluconazole-resistant, clinical Candida albicans strains is caused by mutations in a trans-regulatory factor. J. Bacteriol. 182: 400404.
118. Wirsching, S.,, G. P. Moran,, D. J. Sullivan,, D. C. Coleman, and, J. Morschhäuser. 2001. MDR1-mediated drug resistance in Candida dubliniensis. Antimicrob. Agents Chemother. 45: 34163421.
119. Yang, X.,, D. Talibi,, S. Weber,, G. Poisson, and, M. Raymond. 2001. Functional isolation of the Candida albicans FCR3 gene encoding a bZip transcription factor homologous to Saccharomyces cerevisiae Yap3p. Yeast 18: 12171225.
120. Zhang, X.,, M. De Micheli,, S. T. Coleman,, D. Sanglard, and, W. S. Moye-Rowley. 2000. Analysis of the oxidative stress regulation of the Candida albicans transcription factor, Cap1p. Mol. Microbiol. 36: 618629.
121. Znaidi, S.,, X. De Deken,, S. Weber,, T. Rigby,, A. Nantel, and, M. Raymond. 2007. The zinc cluster transcription factor Tac1p regulates PDR16 expression in Candida albicans. Mol. Microbiol. 66: 440452.
122. Znaidi, S.,, K. S. Barker,, S. Weber,, A. M. Alarco,, T. T. Liu,, G. Boucher,, P. D. Rogers, and, M. Raymond. 2009. Identification of the Candida albicans Cap1p regulon. Eukaryot. Cell 8:806–820.
123. Znaidi, S.,, S. Weber,, O. Z. Al-Abdin,, P. Bomme,, S. Saidane,, S. Drouin,, S. Lemieux,, X. De Deken,, F. Robert, and, M. Raymond. 2008. Genomewide location analysis of Candida albicans Upc2p, a regulator of sterol metabolism and azole drug resistance. Eukaryot. Cell 7: 836847.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error