1887

Chapter 14 : Molecular Principles of Antifungal Drug Resistance

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
Zoomout

Molecular Principles of Antifungal Drug Resistance, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555815776/9781555813680_Chap14-1.gif /docserver/preview/fulltext/10.1128/9781555815776/9781555813680_Chap14-2.gif

Abstract:

The most common agents of fungal infections include , , and , since these are ubiquitous and commensal fungal colonizers. This chapter focuses on the treatment of these three important fungal diseases, with an emphasis on . However, the effectiveness of these therapies against other fungal infections also needs to be considered. Currently available antifungal drugs can be grouped into four main categories-polyenes, nucleic acid synthesis inhibitors, ergosterol biosynthesis inhibitors (EBI), and echinocandins. The polyenes are a class of compounds with an amphipathic nature. The echinocandin caspofungin has only recently become clinically available, and so the number of strains with caspofungin resistance, with or without cross-resistance to other echinocandins, is limited. The chapter summarizes the current knowledge about the regulation of resistance in sand in other yeast species. In addition to the antifungal drug resistance function of CaMDR1, the other genes have oxidoreductive functions (GRP2 and IFD5) or are potentially involved in pyridoxine (vitamin B) synthesis (IPF5987 and SNZ1). One of the most important host factors in treating a fungal infection is the patient’s compliance with the drug regimen. Resistance to antifungal drugs has been observed with the azoles and with 5FC. The molecular mechanisms of resistance of to azole drugs, including alterations in the target enzyme and in drug efflux pumps, have been well defined.

Citation: Sanglard D, White T. 2006. Molecular Principles of Antifungal Drug Resistance, p 197-212. In Heitman J, Filler S, Edwards, Jr. J, Mitchell A (ed), Molecular Principles of Fungal Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555815776.ch14

Key Concept Ranking

Transcription Start Site
0.55685323
RNA Polymerase II
0.49102142
Cell Wall Biosynthesis
0.42062598
0.55685323
Highlighted Text: Show | Hide
Loading full text...

Full text loading...

Figures

Image of Figure 1.
Figure 1.

Azole interactions with fungal cells. Azole antifungals interact with a fungal cell in several ways. First, azole drugs enter the cell. There are conflicting data concerning the mechanisms of import. The azoles then inhibit the azole target enzyme Erg11. Inhibition of that enzyme alters sterol synthesis, which alters membrane sterols, replacing ergo-sterol with 14-α methyl sterols. Azoles are removed from the cell by two types of efflux pump, the ABC transporters, including Cdr1 and Cdr2, and the major facilitators, including Mdr1 and potentially Flu1. Mechanisms of resistance include alterations in and , including mutations and changes in gene expression (boxes outlined in gray).

Citation: Sanglard D, White T. 2006. Molecular Principles of Antifungal Drug Resistance, p 197-212. In Heitman J, Filler S, Edwards, Jr. J, Mitchell A (ed), Molecular Principles of Fungal Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555815776.ch14
Permissions and Reprints Request Permissions
Download as Powerpoint

References

/content/book/10.1128/9781555815776.ch14
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. Albertson, G. D.,, M. Niimi,, R. D. Cannon, and, H. F. Jenkinson. 1996. Multiple efflux mechanisms are involved in Candida albicans fluconazole resistance. Antimicrob. Agents Chemother. 40:28352841.
4. Bader, T.,, B. Bodendorfer,, K. Schroppel, and, J. Morschhauser. 2003. Calcineurin is essential for virulence in Candida albicans. Infect. Immun. 71:53445354.
5. Baillie, G. S., and, L. J. Douglas. 2000. Matrix polymers of Candida biofilms and their possible role in biofilm resistance to antifungal agents. J. Antimicrob. Chemother. 46:397403.
6. Balzi, E., and, A. Goffeau. 1994. Genetics and biochemistry of yeast multidrug resistance. Biochim. Biophys. Acta 1187:152162.
7. Balzi, E.,, M. Wang,, S. Leterme,, L. Van Dyck, and, A. Goffeau. 1994. PDR5, a novel yeast multidrug resistance-conferring transporter controlled by the transcription regulator PDR1. J. Biol. Chem. 269:22062214.
8. 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.
9. Blankenship, J. R.,, F. L. Wormley,, M. K. Boyce,, W. A. Schell,, S. G. Filler,, J. R. Perfect, and, J. Heitman. 2003. Calcineurin is essential for Candida albicans survival in serum and virulence. Eukaryot. Cell 2:422430.
10. Bonilla, M., and, K. W. Cunningham. 2003. Mitogen-activated protein kinase stimulation of Ca2+ signaling is required for survival of endoplasmic reticulum stress in yeast. Mol. Biol. Cell 14:42964305.
11. Bonilla, M.,, K. K. Nastase, and, K. W. Cunningham. 2002. Essential role of calcineurin in response to endoplasmic reticulum stress. EMBO J. 21:23432353.
12. Bouchara, J. P.,, R. Zouhair,, S. Le Boudouil,, G. Renier,, R. Filmon,, D. Chabasse,, J. N. Hallet, and, A. Defontaine. 2000. In-vivo selection of an azole-resistant petite mutant of Candida glabrata. J. Med. Microbiol. 49:977984.
13. Brown, M. S., and, J. L. Goldstein. 1997. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89:331340.
14. Brun, S.,, C. Aubry,, O. Lima,, R. Filmon,, T. Berges,, D. Chabasse, and, J. P. Bouchara. 2003. Relationships between respiration and susceptibility to azole anti-fungals in Candida glabrata. Antimicrob. Agents. Chemother. 47:847853.
15. Brun, S.,, T. Berges,, P. Poupard,, C. Vauzelle-Moreau,, G. Renier,, D. Chabasse, and, J. P. Bouchara. 2004. Mechanisms of azole resistance in petite mutants of Candida glabrata. Antimicrob. Agents Chemother. 48:17881796.
16. 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.
17. Calvet, H. M.,, M. R. Yeaman, and, S. G. Filler. 1997. Reversible fluconazole resistance in Candida albicans: a potential in vitro model. Antimicrob. Agents Chemother. 41:535539.
18. Castano, I.,, R. Kaur,, S. Pan,, R. Cregg,, L. Penas Ade,, N. Guo,, M. C. Biery,, N. L. Craig, and, B. P. Cormack. 2003. Tn7-based genome-wide random insertional muta-genesis of Candida glabrata. Genome Res. 13:905915.
19. 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.
20. 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.
21. Cowen, L. E.,, L. M. Kohn, and, J. B. Anderson. 2001. Divergence in fitness and evolution of drug resistance in experimental populations of Candida albicans. J. Bacteriol. 183:29712978.
22. Cowen, L. E.,, A. Nantel,, M. S. Whiteway,, D. Y. Thomas,, D. C. Tessier,, L. M. Kohn, and, J. B. Anderson. 2002. Population genomics of drug resistance in Candida albicans. Proc. Natl. Acad. Sci. USA 99:92849289.
23. Cruz, M. C.,, A. L. Goldstein,, J. R. Blankenship,, M. Del Poeta,, D. Davis,, M. E. Cardenas,, J. R. Perfect,, J. H. McCusker, and, J. Heitman. 2002. Calcineurin is essential for survival during membrane stress in Candida albi-cans. EMBO J. 21:546559.
24. Davis, D. A.,, V. M. Bruno,, L. Loza,, S. G. Filler, and, A. P. Mitchell. 2002. Candida albicans Mds3p, a conserved regulator of pH responses and virulence identified through insertional mutagenesis. Genetics 162:15731581.
25. De Deken, X., and, M. Raymond. 2004. Constitutive activation of the PDR16 promoter in a Candida albicans azole-resistant clinical isolate overexpressing CDR1 and CDR2. Antimicrob. Agents Chemother. 48:27002703.
26. 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.
27. Devaux, F.,, E. Carvajal,, S. Moye-Rowley, and, C. Jacq. 2002. Genome-wide studies on the nuclear PDR3-controlled response to mitochondrial dysfunction in yeast. FEBS Lett. 515:2528.
28. Diaz-Guerra, T. M.,, E. Mellado,, M. Cuenca-Estrella, and, J. L. Rodriguez-Tudela. 2003. A point mutation in the 14α-sterol demethylase gene cyp51A contributes to itraconazole resistance in Aspergillus fumigatus. Antimicrob. Agents Chemother. 47:11201124.
29. Douglas, C. M.,, J. A. Marrinan,, W. Li, and, M. B. Kurtz. 1994. A Saccharomyces cerevisiae mutant with echinocandin-resistant 1,3-β-D-glucan synthase. J. Bacteriol. 176:56865696.
30. Edlind, T.,, L. Smith,, K. Henry,, S. Katiyar, and, J. Nickels. 2002. Antifungal activity in Saccharomyces cerevisiae is modulated by calcium signalling. Mol. Microbiol. 46:257268.
31. Franz, R.,, S. L. Kelly,, D. C. Lamb,, D. E. Kelly,, M. Ruhnke, and, J. Morschhauser. 1998. Multiple molecular mechanisms contribute to a stepwise development of fluconazole resistance in clinical Candida albicans strains. Antimicrob. Agents Chemother. 42:30653072.
32. Gaur, N. A.,, N. Puri,, N. Karnani,, G. Mukhopadhyay,, S. K. Goswami, and, R. Prasad. 2004. Identification of a negative regulatory element which regulates basal transcription of a multidrug resistance gene CDR1 of Candida albicans. FEMS Yeast Res. 4:389399.
33. Geraghty, P., and, K. Kavanagh. 2003. Disruption of mitochondrial function in Candida albicans leads to reduced cellular ergosterol levels and elevated growth in the presence of amphotericin B. Arch. Microbiol. 179:295300.
34. Graybill, J. R.,, E. Montalbo,, W. R. Kirkpatrick,, M. F. Luther,, S. G. Revankar, and, T. F. Patterson. 1998. Fluconazole versus Candida albicans: a complex relationship. Antimicrob. Agents Chemother. 42:29382942.
35. Gyurko, C.,, U. Lendenmann,, R. F. Troxler, and, F. G. Oppenheim. 2000. Candida albicans mutants deficient in respiration are resistant to the small cationic salivary antimicrobial peptide histatin 5. Antimicrob. Agents Chemother. 44:348354.
36. Hawser, S. P.,, H. Norris,, C. J. Jessup, and, M. A. Ghannoum. 1998. Comparison of a 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenyl-amino)carbonyl]-2 H- tetrazolium hydroxide (XTT) colorimetric method with the Standardized National Committee for Clinical Laboratory Standards method of testing clinical yeast isolates for susceptibility to antifungal agents. J. Clin. Microbiol. 36:14501452.
37. Hikkel, I.,, A. Lucau-Danila,, T. Delaveau,, P. Marc,, F. Devaux, and, C. Jacq. 2003. A general strategy to uncover transcription factor properties identifies a new regulator of drug resistance in yeast. J. Biol. Chem. 278:1142711432.
38. Hooshdaran, M. Z.,, K. S. Barker,, G. M. Hilliard,, H. Kusch,, J. Morschhauser, and, P. D. Rogers. 2004. Proteomic analysis of azole resistance in Candida albi-cans clinical isolates. Antimicrob. Agents Chemother. 48:27332735.
39. Hope, W. W.,, L. Tabernero,, D. W. Denning, and, M. J. Anderson. 2004. Molecular mechanisms of primary resistance to flucytosine in Candida albicans. Antimicrob. Agents Chemother. 48:43774386.
40. Hull, C. M.,, R. M. Raisner, and, A. D. Johnson. 2000. Evidence for mating of the “asexual” yeast Candida albicans in a mammalian host. Science 289:307310.
41. Karababa, M.,, A. T. Coste,, B. Rognon,, J. Bille, and, D. Sanglard. 2004. Comparison of gene expression profiles of Candida albicans azole-resistant clinical isolates and laboratory strains exposed to drugs inducing multidrug transporters. Antimicrob. Agents Chemother. 48:30643079.
42. Karnani, N.,, N. A. Gaur,, S. Jha,, N. Puri,, S. Krishnamurthy,, 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.
43. Kaur, R.,, I. Castano, and, B. P. Cormack. 2004. Functional genomic analysis of fluconazole susceptibility in the pathogenic yeast Candida glabrata: roles of calcium signaling and mitochondria. Antimicrob. Agents Chemother. 48:16001613.
44. Koh, J. Y.,, P. Hajek, and, D. M. Bedwell. 2001. Overproduction of PDR3 suppresses mitochondrial import defects associated with a TOM70 null mutation by increasing the expression of TOM72 in Saccharomyces cerevisiae. Mol. Cell. Biol. 21:75767586.
45. Kren, A.,, Y. M. Mamnun,, B. E. Bauer,, C. Schuller,, H. Wolfger,, K. Hatzixanthis,, M. Mollapour,, C. Gregori,, P. Piper, and, K. Kuchler. 2003. War1p, a novel transcription factor controlling weak acid stress response in yeast. Mol. Cell. Biol. 23:17751785.
46. Kusch, H.,, K. Biswas,, S. Schwanfelder,, S. Engelmann,, P. D. Rogers,, M. Hecker, and, J. Morschhauser. 2004. A proteomic approach to understanding the development of multidrug-resistant Candida albicans strains. Mol. Genet. Genomics 271:554565.
47. Lopez–Ribot, J.,, R. K. McAtee,, L. Lee,, W. R. Kirkpatrick,, T. C. White,, D. Sanglard, and, T. F. Patterson. 1998. Distinct patterns of gene expression associated with the development of fluconazole resistance in serial Candida albicans isolates from HIV-infected patients with oropharyngeal candidiasis. Antimicrob. Agents Chemother. 42:29322937.
48. Magee, B. B., and, P. T. Magee. 2000. Induction of mating in Candida albicans by construction of MTL a and MTL strains. Science 289:310313.
49. Mann, P. A.,, R. M. Parmegiani,, S. Q. Wei,, C. A. Mendrick,, X. Li,, D. Loebenberg,, B. DiDomenico,, R. S. Hare,, S. S. Walker, and, P. M. McNicholas. 2003. Mutations in Aspergillus fumigatus resulting in reduced susceptibility to posaconazole appear to be restricted to a single amino acid in the cytochrome P450 14α-demethylase. Antimicrob. Agents Chemother. 47:577581.
50. Marchetti, O.,, J. M. Entenza,, D. Sanglard,, J. Bille,, M. P. Glauser, and, P. Moreillon. 2000. Fluconazole plus cyclosporine: a fungicidal combination effective against experimental endocarditis due to Candida albicans. Antimicrob. Agents Chemother. 44:29322938.
51. Marchetti, O.,, P. Moreillon,, M. P. Glauser,, J. Bille, and, D. Sanglard. 2000. Potent synergism of the combination of fluconazole and cyclosporine in Candida albicans. Antimicrob. Agents Chemother. 44:23732381.
52. Marichal, P.,, L. Koymans,, S. Willemsens,, D. Bellens,, P. Verhasselt,, W. Luyten,, M. Borgers,, F. C. S. Ramaekers,, F. C. Odds, and, H. Vanden Bossche. 1999. Contribution of mutations in the cytochrome P450 14α-demethylase (Erg11p, Cyp51p) to azole resistance in Candida albi-cans. Microbiology 45:27012713.
53. Marr, K. A.,, C. N. Lyons,, K. Ha,, T. R. Rustad, and, T. C. White. 2001. Inducible azole resistance associated with a heterogeneous phenotype in Candida albicans. Antimicrob. Agents Chemother. 45:5259.
54. Marr, K. A.,, C. N. Lyons,, T. R. Rustad,, R. A. Bowden, and, T. C. White. 1998. Rapid, transient fluconazole resistance in Candida albicans is associated with increased mRNA levels of CDR. Antimicrob. Agents Chemother. 42:25842589.
55. Mellads, E.,, G. Garcia-Effron,, L. Alcazar-Fuoli,, M. Cuenca-Estrella, and, J. L. Rodriguez-Tudela. 2004. Substitutions at methionine 220 in the 14 alpha-sterol demethylase (Cyp51A) of Aspergillus fumigatus are responsible for resistance in vitro to azole antifungal drugs. Antimicrob. Agents Chemother. 48:27472750.
56. Mendizabal, I.,, G. Rios,, J. M. Mulet,, R. Serrano, and, I. F. de Larrinoa. 1998. Yeast putative transcription factors involved in salt tolerance. FEBS Lett. 425:323328.
57. Miyazaki, Y.,, A. Geber,, H. Miyazaki,, D. Falconer,, T. Parkinson,, C. Hitchcock,, B. Grimberg,, K. Nyswaner, and, J. E. Bennett. 1999. Cloning, sequencing, expression and allelic sequence diversity of ERG3 (C-5 sterol desaturase gene) in Candida albicans. Gene 236:4351.
58. Mondon, P.,, R. Petter,, G. Amalfitano,, R. Luzzati,, E. Concia,, I. Polacheck, and, K. J. Kwon-Chung. 1999. Heteroresistance to fluconazole and voriconazole in Cryptococcus neoformans. Antimicrob. Agents Chemother. 43:18561861.
59. Moran, G. P.,, D. Sanglard,, S. Donnelly,, D. B. Shanley,, D. J. Sullivan, and, D. C. Coleman. 1998. Identification and expression of multidrug transporters responsible for fluconazole resistance in Candida dubliniensis. Antimicrob. Agents Chemother. 42:18191830.
60. Nakamura, K.,, M. Niimi,, K. Niimi,, A. R. Holmes,, J. E. Yates,, A. Decottignies,, B. C. Monk,, A. Goffeau, and, R. D. Cannon. 2001. Functional expression of Candida albicans drug efflux pump Cdr1p in a Saccharomyces cerevisiae strain deficient in membrane transporters. Antimicrob. Agents Chemother. 45:33663374.
61. National Committee for Clinical Laboratory Standards. 2002. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Molds. Approved Standard. NCCLS document M38-A. National Committee for Clinical Laboratory Standards, Wayne, Pa.
62. National Committee for Clinical Laboratory Standards. 1997. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts. Approved Standard. NCCLS document M27-A. National Committee for Clinical Laboratory Standards, Wayne, Pa.
63. Noel, T.,, F. Francois,, P. Paumard,, C. Chastin,, D. Brethes, and, J. Villard. 2003. Flucytosine-fluconazole cross-resistance in purine-cytosine permease-deficient Candida lusitaniae clinical isolates: indirect evidence of a fluconazole uptake transporter. Antimicrob. Agents Chemother. 47:12751284.
64. 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. 44:196199.
65. 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.
66. Posteraro, B.,, M. Sanguinetti,, D. Sanglard,, M. La Sorda,, S. Boccia,, L. Romano,, G. Morace, and, G. Fadda. 2003. Identification and characterization of a Cryptococcus neoformans ATP binding cassette (ABC) transporter-encoding gene, CnAFR1, involved in the resistance to fluconazole. Mol. Microbiol. 47:357371.
67. Pujol, C.,, S. A. Messer,, M. Pfaller, and, D. R. Soll. 2003. Drug resistance is not directly affected by mating type locus zygosity in Candida albicans. Antimicrob. Agents Chemother. 47:12071212.
68. Pujol, C.,, M. A. Pfaller, and, D. R. Soll. 2004. Flucytosine resistance is restricted to a single genetic clade of Candida albicans. Antimicrob. Agents Chemother. 48:262266.
69. Pujol, C.,, J. Reynes,, F. Renaud,, M. Raymond,, M. Tibayrenc,, F. J. Ayala,, F. Janbon,, M. Mallie, and, J. M. Bastide. 1993. The yeast Candida albicans has a clonal mode of reproduction in a population of infected human immunodeficiency virus-positive patients. Proc. Natl. Acad. Sci. USA 90:94569459.
70. Ramage, G.,, S. Bachmann,, T. F. Patterson,, B. L. Wickes, and, R. J., L. Lopez. 2002. Investigation of multidrug efflux pumps in relation to fluconazole resistance in Candida albicans biofilms. J. Antimicrob. Chemother. 49:973980.
71. Ramage, G.,, K. vande., B. L. Wickes, and, J. L. Lopez-Ribot. 2001. Standardized method for in vitro antifungal susceptibility testing of Candida albicans biofilms. Antimicrob. Agents Chemother. 45:24752479.
72. Rex, J. H.,, P. W. Nelson,, V. L. Paetznick,, M. Lozano-Chiu,, A. Espinel-Ingroff, and, E. J. Anaissie. 1998. Optimizing the correlation between results of testing in vitro and therapeutic outcome in vivo for fluconazole by testing critical isolates in a murine model of invasive candidiasis. Antimicrob. Agents Chemother. 42:129134.
73. Rex, J. H., and, M. A. Pfaller. 2002. Has antifungal susceptibility testing come of age? Clin. Infect. Dis. 35:982989.
74. Rodero, L.,, E. Mellado,, A. C. Rodriguez,, A. Salve,, L. Guelfand,, P. Cahn,, M. Cuenca-Estrella,, G. Davel, and, J. L. Rodriguez-Tudela. 2003. G484S amino acid substitution in lanosterol 14α-demethylase (ERG11) is related to fluconazole resistance in a recurrent Cryptococcus neoformans clinical isolate. Antimicrob. Agents Chemother. 47:36533656.
75. Rogers, P. D., and, K. S. Barker. 2002. Evaluation of differential gene expression in fluconazole-susceptible and -resistant isolates of Candida albicans by cDNA microarray analysis. Antimicrob. Agents Chemother. 46:34123417.
76. 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.
77. Rustad, T. R.,, D. A. Stevens,, M. A. Pfaller, and, T. C. White. 2002. Homozygosity at the Candida albicans MTL locus associated with azole resistance. Microbiology 148:10611072.
78. Sanglard, D., and, J. Bille. 2002. Current understanding of the mode of action and of resistance mechanisms to conventional and emerging antifungal agents for treatment of Candida infections, p. 349–383. In R. Calderone (ed.), Candida and Candidiasis. ASM Press, Washington, D.C.
79. 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.
80. 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. Antimicrob. Agents Chemother. 43:27532765.
81. Sanglard, D.,, F. Ischer,, L. Koymans, and, J. Bille. 1998. Amino acid substitutions in the cytochrome P450 lanosterol 14α-demethylase (CYP51A1) from azole-resistant Candida albicans clinical isolates contributing to the resistance to azole antifungal agents. Antimicrob. Agents Chemother. 42:241253.
82. 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.
83. 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.
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,, T. Parkinson,, D. Falconer, and, J. Bille. 2003. Candida albicans mutations in the ergosterol biosynthetic pathway and resistance to several antifungal agents. Antimicrob. Agents Chemother. 47:24042412.
86. 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.
87. Sanglard, D., and, F. C. Odds. 2002. Resistance of Candida species to antifungal agents molecular mechanisms and clinical consequences. Lancet Infect. Dis. 2:7385.
88. Schjerling, P., and, S. Holmberg. 1996. Comparative amino acid sequence analysis of the C6 zinc cluster family of transcriptional regulators. Nucleic Acids Res. 24:45994607.
89. Schuetzer-Muehlbauer, M.,, B. Willinger,, G. Krapf,, S. Enzinger,, E. Presterl, and, K. Kuchler. 2003. The Candida albicans Cdr2p ATP-binding cassette (ABC) transporter confers resistance to caspofungin. Mol. Microbiol. 48:225235.
90. 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.
91. Slaven, J. W.,, M. J. Anderson,, D. Sanglard,, G. K. Dixon,, J. Bille,, I. S. Roberts, and, D. W. Denning. 2002. Induced expression of a novel Aspergillus fumigatus ABC transporter gene, atrF, in response to itraconazole. Fungal Genet. Biol. 36:199206.
92. Sugar, A. M.,, C. A. Hitchcock,, P. F. Troke, and, M. Picard. 1995. Combination therapy of murine invasive candidiasis with fluconazole and amphotericin B. Antimicrob. Agents Chemother. 39:598601.
93. 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.
94. White, T. C. 1997. Increased mRNA levels of ERG16, CDR, and MDR1 correlate with increases in azole resistance in Candida albicans isolates from a patient infected with human immunodeficiency virus. Antimicrob. Agents Chemother. 41:14821487.
95. 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.
96. White, T. C.,, S. Holleman,, F. Dy,, L. F. Mirels, and, D. A. Stevens. 2002. Resistance mechanisms in clinical isolates of Candida albicans. Antimicrob. Agents Chemother. 46:17041713.
97. 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.
98. White, T. C.,, M. A. Pfaller,, R. G. Rinaldi,, J. Smith, and, S. W. Redding. 1997. Stable azole drug resistance associated with a substrain of Candida albicans from an HIV-infected patient. Oral Dis. 3:S102S109.
99. Wirsching, S.,, S. Michel,, G. Kohler, and, J. Morschhauser. 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.
100. Wirsching, S.,, S. Michel, and, J. Morschhauser. 2000. Targeted gene disruption in Candida albicans wild-type strains: the role of the MDR1 gene in fluconazole resistance of clinical Candida albicans isolates. Mol. Microbiol. 36:856865.
101. 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.

Tables

Generic image for table
Table 1.

Transcription factors regulating resistance

Citation: Sanglard D, White T. 2006. Molecular Principles of Antifungal Drug Resistance, p 197-212. In Heitman J, Filler S, Edwards, Jr. J, Mitchell A (ed), Molecular Principles of Fungal Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555815776.ch14

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