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Chapter 44 : Molecular Detection of Antifungal Resistance

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Abstract:

The increasing need for clinically relevant antifungal susceptibility assays is driven by three recent developments in medical mycology: (i) the increasing incidence of fungal infection due to immunosuppression (associated with AIDS, organ and tissue transplantation, and aggressive treatments for cancer and autoimmune disease), (ii) the expanding number of antifungals with both shared and distinct mechanisms of action, and (iii) the recognition of wide variation in susceptibility due to both intrinsic and acquired antifungal resistance. With respect to disease-causing fungi, some of these conditions apply, but clearly in limited and specific ways. First, for most fungal pathogens and antifungals, the development of resistance during treatment is rare. Second, relatively few studies have directly examined the clinical relevance of antifungal susceptibility data. The majority of these mutations involve a single Cyp51A residue, G54, although at least four additional residues have also been implicated. The currently known mutations associated with azole resistance in Erg11 and Cyp51A are dispersed over 1.2 kbp of primary sequence. Echinocandins (caspofungin, micafungin, and anidulafungin) are the most recently introduced class of antifungals but are highly promising due to their mechanism-based selective toxicity. A great deal has been learned in recent years regarding molecular mechanisms of antifungal resistance, particularly in the yeasts and and the mold . In addition, simple and cost-effective approaches to measuring RNA expression and sequencing DNA are required.

Citation: Edlind T. 2011. Molecular Detection of Antifungal Resistance, p 677-684. In Persing D, Tenover F, Tang Y, Nolte F, Hayden R, van Belkum A (ed), Molecular Microbiology. ASM Press, Washington, DC. doi: 10.1128/9781555816834.ch44

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Reverse Transcriptase PCR
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Transcription Factor Upc2
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Integral Membrane Proteins
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Figures

Image of FIGURE 1
FIGURE 1

Anatomy of transcriptional activator Pdr1, based on homology to Pdr1 and Pdr3. Gain-of-function mutations (indicated by vertical bars [ ; S. Katiyar and T. Edlind, unpublished data]) result in increased expression of MDR transporter genes whose products are responsible for azole efflux. Shaded areas indicate approximate locations of the DNA binding (DB), inhibitory, and activation domains. The total lengths range from 976 to 1,107 amino acids.

Citation: Edlind T. 2011. Molecular Detection of Antifungal Resistance, p 677-684. In Persing D, Tenover F, Tang Y, Nolte F, Hayden R, van Belkum A (ed), Molecular Microbiology. ASM Press, Washington, DC. doi: 10.1128/9781555816834.ch44
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Image of FIGURE 2
FIGURE 2

Alignment of Erg11 and Cyp51A sequences. Alignment was generated by ClustalW (vertical bars, identity; dots, conservative differences; hyphens, gaps introduced to optimize alignment). Residues mutated in azole-resistant clinical isolates ( ; for a review, see reference and references therein) are underlined, and the mutation is indicated above or below . Note that many of these mutations have not been experimentally confirmed to confer resistance.

Citation: Edlind T. 2011. Molecular Detection of Antifungal Resistance, p 677-684. In Persing D, Tenover F, Tang Y, Nolte F, Hayden R, van Belkum A (ed), Molecular Microbiology. ASM Press, Washington, DC. doi: 10.1128/9781555816834.ch44
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Image of FIGURE 3
FIGURE 3

Mutations conferring echinocandin resistance in and the indicated species localize to Fks1 or Fks2 hot spots 1 and 2. The mutated residue is underlined, with the observed change indicated below the residue. Dots indicate identity to the Fks1 residue. See text for references.

Citation: Edlind T. 2011. Molecular Detection of Antifungal Resistance, p 677-684. In Persing D, Tenover F, Tang Y, Nolte F, Hayden R, van Belkum A (ed), Molecular Microbiology. ASM Press, Washington, DC. doi: 10.1128/9781555816834.ch44
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References

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1. Akins, R. A. 2005. An update on antifungal targets and mechanisms of resistance in Candida albicans. Med. Mycol. 43:285318.
2. Arikan, S. 2007. Current status of antifungal susceptibility testing methods. Med. Mycol. 45:569587.
3. Baixench, M. T.,, N. Aoun,, M. Desnos-Ollivier,, D. Garcia-Hermoso,, S. Bretagne,, S. Ramires,, C. Piketty, and, E. Dannaoui. 2007. Acquired resistance to echino-candins in Candida albicans: case report and review. J. Antimicrob. Chemother. 59:10761083.
4. Balashov, S. V.,, R. Gardiner,, S. Park, and, D. S. Perlin. 2005. Rapid, high-throughput, multiplex, real-time PCR for identification of mutations in the cyp51A gene of Aspergillus fumigatus that confer resistance to itraconazole. J. Clin. Microbiol. 43:214222.
5. Balashov, S. V.,, S. Park, and, D. S. Perlin. 2006. Assessing resistance to the echinocandin antifungal drug caspofungin in Candida albicans by profiling mutations in FKS1. Antimicrob. Agents Chemother. 50:20582063.
6. Barchiesi, F.,, D. Calabrese,, D. Sanglard,, L. Falconi Di Francesco,, F. Caselli,, D. Giannini,, A. Giacometti,, S. Ga-vaudan, and, G. Scalise. 2000. Experimental induction of fluconazole resistance in Candida tropicalis ATCC 750. Antimicrob. Agents Chemother. 44:15781584.
7. 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.
8. Carvajal, E.,, H. B. van den Hazel,, A. Cybularz-Kolaczkowska,, E. Balzi, and, A. Goffeau. 1997. Molecular and phenotypic characterization of yeast PDR1 mutants that show hyperactive transcription of various ABC multidrug transporter genes. Mol. Gen. Genet. 256:406415.
9. Cernicka, J.,, and J. Subik. 2006. Resistance mechanisms in fluconazole-resistant Candida albicans isolates from vaginal candidiasis. Int. J. Antimicrob. Agents 27:403408.
10. Chen, J.,, H. Li,, R. Li,, D. Bu, and, Z. Wan. 2005. Mutations in the cyp51A gene and susceptibility to itracon-azole in Aspergillus fumigatus serially isolated from a patient with lung aspergilloma. J. Antimicrob. Chemother. 55:3137.
11. Coste, A.,, V. Turner,, F. Ischer,, J. Morschhauser,, A. Forche,, A. Selmecki,, J. Berman,, J. Bille, and, D. Sang-lard. 2006. A mutation in Tac1p, a transcription factor regulating CDR1 and CDR2, is coupled with loss of het-erozygosity at chromosome 5 to mediate antifungal resistance in Candida albicans. Genetics 172:21392156.
12. 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.
13. Crothers, K.,, C. B. Beard,, J. Turner,, G. Groner,, M. Fox,, A. Morris,, S. Eiser, and, L. Huang. 2005. Severity and outcome of HIV-associated Pneumocystis pneumonia containing Pneumocystis jirovecii dihydropteroate synthase gene mutations. AIDS 19:801805.
14. Denning, D. W. 2002. Echinocandins: a new class of antifungal. J. Antimicrob. Chemother. 49:889891.
15. Desnos-Ollivier, M.,, S. Bretagne,, D. Raoux,, D. Hoin-ard,, F. Dromer,, E. Dannaoui, and the European Committee on Antibiotic Susceptibility Testing. 2008. Mutations in the fks1 gene in Candida albicans, C. tropicalis, and C. krusei correlate with elevated caspofungin MICs uncovered in AM3 medium using the method of the European Committee on Antibiotic Susceptibility Testing. Antimicrob. Agents Chemother. 52:30923098.
16. Dodgson, A. R.,, K. J. Dodgson,, C. Pujol,, M. A. Pfaller, and, D. R. Soll. 2004. Clade-specific flucytosine resistance is due to a single nucleotide change in the FUR1 gene of Candida albicans. Antimicrob. Agents Chemother. 48:22232227.
17. Douglas, C. M. 2001. Fungal (3(1,3)-D-glucan synthesis. Med. Mycol. 39(Suppl.):5566.
18. Dunkel, N.,, J. Blass,, P. D. Rogers, and, J. Morschhauser. 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.
19. Dunkel, N.,, T. T. Liu,, K. S. Barker,, R. Homayouni,, J. Morschhauser, 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.
20. Edlind, T. D. 2007. Emergence and evolution of antifungal resistance, p. 297-306. In F. Baquero,, C. Nombela,, G. H. Cassell, and, J. A. Gutierrez-Fuentes (ed.), Evolutionary Biology of Bacterial and Fungal Pathogens. ASM Press, Washington, DC.
21. Ellis, D. 2002. Amphotericin B: spectrum and resistance. J. Antimicrob. Chemother. 49(Suppl. A):710.
22. Fothergill, A. W.,, M. G. Rinaldi, and, D. A. Sutton. 2006. Antifungal susceptibility testing. Infect. Dis. Clin. N. Am. 20:699709.
23. Garcia-Effron, G.,, A. Dilger,, L. Alcazar-Fuoli,, S. Park,, E. Mellado, and, D. S. Perlin. 2008. Rapid detection of triazole antifungal resistance in Aspergillus fumigatus. J. Clin. Microbiol. 46:12001206.
24. Gygax, S. E.,, J. P. Vermitsky,, S. G. Chadwick,, M. J. Self,, J. A. Zimmerman,, E. Mordechai,, M. E. Adelson, and, J. P. Trama. 2008. Antifungal resistance of Candida glabrata vaginal isolates and development of a quantitative reverse transcription-PCR-based azole susceptibility assay. Antimicrob. Agents Chemother. 52:34243426.
25. Hachem, R.,, H. Hanna,, D. Kontoyiannis,, Y. Jiang, and, I. Raad. 2008. The changing epidemiology of invasive candidiasis: Candida glabrata and Candida krusei as the leading causes of candidemia in hematologic malignancy. Cancer 112:24932499.
26. Hazen, K. C.,, J. Stei,, C. Darracott,, A. Breathnach,, J. May, and, S. A. Howell. 2005. Isolation of cholesterol-dependent Candida glabrata from clinical specimens. Diagn. Microbiol. Infect. Dis. 52:3537.
27. Henry, K. W.,, J. T. Nickels, and, T. D. Edlind. 2000. Upregulation of ERG genes in Candida species by azoles and other sterol biosynthesis inhibitors. Antimicrob. Agents Chemother. 44:26932700.
28. 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.
29. Howard, S. J.,, I. Webster,, C. B. Moore,, R. E. Gardiner,, S. Park,, D. S. Perlin, and, D. W. Denning. 2006. Multi-azole resistance in Aspergillus fumigatus. Int. J. Antimicrob. Agents 28:450453.
30. Huang, L.,, D. A. Welsh,, R. F. Miller,, C. B. Beard,, G. G. Lawrence,, M. Fox,, A. Swartzman,, M. R. Bensley,, D. Carbonnet,, J. L. Davis,, A. Chi,, B. J. Yoo, and, J. L. Jones. 2006. Pneumocystis jirovecii dihydropteroate syn-thase gene mutations and human immunodeficiency virus-associated Pneumocystis pneumonia. J. Eukaryot. Microbiol. 53(Suppl. 1):S114S116.
31. Kanafani, Z. A.,, and J. R. Perfect. 2008. Antimicrobial resistance: resistance to antifungal agents: mechanisms and clinical impact. Clin. Infect. Dis. 46:120128.
32. Katiyar, S.,, M. Pfaller, and, T. Edlind. 2006. Candida albicans and Candida glabrata clinical isolates exhibiting reduced echinocandin susceptibility. Antimicrob. Agents Chemother. 50:28922894.
33. 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.
34. Kerridge, D.,, M. Fasoli, and, J. F. Wayman. 1988. Drug resistance in Candida albicans and Candida glabrata. Ann. N. Y. Acad. Sci. 544:245259.
35. Kofla, G.,, and M. Ruhnke. 2007. Development of a new real-time TaqMan PCR assay for quantitative analyses of Candida albicans resistance genes expression. J. Microbiol. Methods 68:178183.
36. Kurtz, M. B.,, and J. H. Rex. 2001. Glucan synthase inhibitors as antifungal agents. Adv. Protein Chem. 56:423475.
37. Lamb, D. C.,, D. E. Kelly,, T. C. White, and, S. L. Kelly. 2000. The R467K amino acid substitution in Candida albicans sterol 14α-demethylase causes drug resistance through reduced affinity. Antimicrob. Agents Chemother. 44:6367.
38. Laverdiere, M.,, R. G. Lalonde,, J. G. Baril,, D. C. Sheppard,, S. Park, and, D. S. Perlin. 2006. Progressive loss of echinocandin activity following prolonged use for treatment of Candida albicans oesophagitis. J. Antimicrob. Chemother. 57:705708.
39. Lopez-Ribot, J. L.,, R. K. McAtee,, S. Perea,, W. R. Kirk-patrick,, M. G. Rinaldi, and, T. F. Patterson. 1999. Multiple resistant phenotypes of Candida albicans coexist during episodes of oropharyngeal candidiasis in human immunodeficiency virus-infected patients. Antimicrob. Agents Chemother. 43:16211630.
40. Lorenz, R. T.,, and L. W. Parks. 1992. Cloning, sequencing, and disruption of the gene encoding sterol C-14 reductase in Saccharomyces cerevisiae. DNA Cell Biol. 11:685692.
41. Ma, L.,, J. A. Kovacs,, A. Cargnel,, A. Valerio,, G. Fantoni, and, C. Atzori. 2002. Mutations in the dihydropteroate synthase gene of human-derived Pneumocystis carinii isolates from Italy are infrequent but correlate with prior sulfa prophylaxis. J. Infect. Dis. 185:15301532.
42. Martinez, M.,, J. L. Lopez-Ribot,, W. R. Kirkpatrick,, S. P. Bachmann,, S. Perea,, M. T. Ruesga, and, T. F. Patterson. 2002. Heterogeneous mechanisms of azole resistance in Candida albicans clinical isolates from an HIV-infected patient on continuous fluconazole therapy for oropharyngeal candidosis. J. Antimicrob. Chemother. 49:515524.
43. Mellado, E.,, G. Garcia-Effron,, L. Alcazar-Fuoli,, W. J. Melchers,, P. E. Verweij,, M. Cuenca-Estrella, and, J. L. Rodriguez-Tudela. 2007. A new Aspergillus fumigatus resistance mechanism conferring in vitro cross-resistance to azole antifungals involves a combination of cyp51A alterations. Antimicrob. Agents Chemother. 51:18971904.
44. Moosa, M.-Y. S.,, G. J. Alangaden,, E. Manavathu, and, P. H. Chandrasekar. 2002. Resistance to amphotericin B does not emerge during treatment for invasive aspergillosis. J. Antimicrob. Chemother. 49:209213.
45. Moran, G. P.,, D. Sanglard,, S. M. 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.
46. Morschhauser, J.,, K. S. Barker,, T. T. Liu,, J. Blaβ-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. 3:16031616.
47. 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.
48. Park, S.,, R. Kelly,, J. N. Kahn,, J. Robles,, M. J. Hsu,, E. Register,, W. Li,, V. Vyas,, H. Fan,, G. Abruzzo,, A. Flattery,, C. Gill,, G. Chrebet,, S. A. Parent,, M. Kurtz,, H. Teppler,, C. M. Douglas, and, D. S. Perlin. 2005. Specific substitutions in the echinocandin target Fks1p account for reduced susceptibility of rare laboratory and clinical Candida sp. isolates. Antimicrob. Agents Chemother. 49:32643273.
49. Pelletier, R.,, J. Peter,, C. Antin,, C. Gonzalez,, L. Wood, and, T. J. Walsh. 2000. Emergence of resistance of Candida albicans to clotrimazole in human immunodeficiency virus-infected children: in vitro and clinical correlations. J. Clin. Microbiol. 38:15631568.
50. Perea, A.,, J. L. Lopez,, 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.
51. Perea, S.,, J. L. Lopez-Ribot,, B. L. Wickes,, W. R. Kirkpatrick,, O. P. Dib,, S. P. Bachmann,, S. M. Keller,, M. Martinez, and, T. F. Patterson. 2002. Molecular mechanisms of fluconazole resistance in Candida dubliniensis isolates from human immunodeficiency virus-infected patients with oropharyngeal candidiasis. Antimicrob. Agents Chemother. 46:16951703.
52. Perlin, D. S. 2007. Resistance to echinocandin-class antifungal drugs. Drug Resist. Updates 10:121130.
53. Pfaller, M. A. 2005. Antifungal susceptibility testing methods. Curr. Drug Targets 6:929943.
54. Pfaller, M. A.,, D. J. Diekema,, L. Ostrosky-Zeichner,, J. H. Rex,, B. D. Alexander,, D. Andes,, S. D. Brown,, V. Chaturvedi,, M. A. Ghannoum,, C. C. Knapp,, D. J. Sheehan, and, T. J. Walsh. 2008. Correlation of MIC with outcome for Candida species tested against caspofungin, anidulafungin, and micafungin: analysis and proposal for interpretive MIC breakpoints. J. Clin. Microbiol. 46:26202629.
55. Pfaller, M. A.,, D. J. Diekema,, J. H. Rex,, A. Espinel-Ingroff,, E. M. Johnson,, D. Andes,, V. Chaturvedi,, M. A. Ghannoum,, F. C. Odds,, M. G. Rinaldi,, D. J. Sheehan,, P. Troke,, T. J. Walsh, and, D. W. Warnock. 2006. Correlation of MIC with outcome for Candida species tested against voriconazole: analysis and proposal for interpretive breakpoints. J. Clin. Microbiol. 44:819826.
56. Rex, J. H.,, M. A. Pfaller,, T. J. Walsh,, V. Chaturvedi,, A. Espinel-Ingroff,, M. A. Ghannoum,, L. L. Gosey,, F. C. Odds,, M. G. Rinaldi,, D. J. Sheehan, and, D. W. Warnock. 2001. Antifungal susceptibility testing: practical aspects and current challenges. Clin. Microbiol. Rev. 14:643658.
57. Rezusta, A.,, C. Aspiroz,, T. Boekhout,, J. J. Cano,, B. Theelen,, J. Guarro, and, M. C. Rubio. 2008. Cholesterol dependent and amphotericin B resistant isolates of a Candida glabrata strain from an intensive care unit patient. Med. Mycol. 46:265268.
58. Sanglard, D.,, F. Ischer,, L. Koymans, and, J. Bille. 1998. Amino acid substitutions in the cytochrome P-450 lan-osterol 14α-demethylase (CYP51A1) from azole-resistant Candida albicans clinical isolates contribute to resistance to azole antifungal agents. Antimicrob. Agents Chemother. 42:241253.
59. 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.
60. Sanglard, D.,, and F. C. Odds. 2002. Resistance of Candida species to antifungal agents: molecular mechanisms and clinical consequences. Lancet Infect. Dis. 2:7385.
61. 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.
62. Slaven, J. W.,, M. J. Anderson,, D. Sanglard,, G. K. Dixon,, J. Bille,, I. S. Roberts, and, D. W. Denning. 2002. Increased expression of a novel Aspergillus fumigatus ABC transporter gene, atrF, in the presence of itraconazole in an itraconazole resistant clinical isolate. Fungal Genet. Biol. 36:199206.
63. Trama, J. P.,, E. Mordechai, and, M. E. Adelson. 2005. Detection of Aspergillus fumigatus and a mutation that confers reduced susceptibility to itraconazole and posaconazole by real-time PCR and pyrosequencing. J. Clin. Microbiol. 43:906908.
64. 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.
65. Vermes, A.,, H.-J. Guchelaar, and, J. Dankert. 2000. Flu-cytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. J. Antimicrob. Chemother. 46:171179.
66. 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.
67. 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.
68. Verweij, P. E.,, E. Mellado, and, W. J. Melchers. 2007. Multiple-triazole-resistant aspergillosis. N. Engl. J. Med. 356:14811483.
69. Whelan, W. L. 1987. The genetic basis of resistance to 5-fluorocytosine in Candida species and Cryptococcus neo-formans. Crit. Rev. Microbiol. 15:4556.
70. 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.
71. White, T. C.,, and P. M. Silver. 2005. Regulation of sterol metabolism in Candida albicans by the UPC2 gene. Biochem. Soc. Trans. 33:12151218.
72. 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.
73. Wiederhold, N. P.,, J. L., Grabinski,, G. Garcia-Effron,, D. S. Perlin, and, S. A. Lee. 2008. Pyrosequencing to detect mutations in FKS1 that confer reduced echinocan-din susceptibility in Candida albicans. Antimicrob. Agents Chemother. 52:41454148.
74. Xiao, L.,, V. Madison,, A. S. Chau,, D. Loebenberg,, R. E. Palermo, and, P. M. McNicholas. 2004. Three-dimensional models of wild-type and mutated forms of cytochrome P450 14α-sterol demethylases from Aspergillus fumigatus and Candida albicans provide insights into po-saconazole binding. Antimicrob. Agents Chemother. 48:568574.

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