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Azole Resistance in Candida glabrata

  • Sarah G. Whaley
  • P. David RogersEmail author
Antimicrobial Development and Drug Resistance (A Pakyz, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Antimicrobial Development and Drug Resistance

Abstract

Candida infections have increased due to the growth and expansion of susceptible patient populations. The azole fluconazole is the most widely prescribed antifungal, but rising rates of clinical resistance among Candida glabrata isolates have greatly limited its utility. A better understanding of the mechanisms of azole antifungal resistance will provide information needed to overcome this clinical problem and reclaim this antifungal class as an option for empiric treatment of Candida infections. By far, the most frequent mechanism of azole resistance in C. glabrata is the overexpression of multidrug transporters due to activating mutations in the gene encoding transcription factor Pdr1. In this review, we will discuss the molecular and genetic basis of azole resistance in C. glabrata with particular attention given to the most recent discoveries in this field.

Keywords

Candida Glabrata Azole Resistance Pdr1 

Notes

Acknowledgments

Our work on azole resistance has been supported by NIH NIAID grant R01 AI058145 awarded to Dr. Rogers

Compliance with Ethical Standards

Conflict of Interest

Drs Whaley and Rogers declare no conflicts of interests.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by the author.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Pfaller MA, Diekema DJ. Epidemiology of invasive mycoses in North America. Crit Rev Microbiol. 2010;36(1):1–53. doi: 10.3109/10408410903241444.CrossRefPubMedGoogle Scholar
  2. 2.
    Azie N, Neofytos D, Pfaller M, Meier-Kriesche HU, Quan SP, Horn D. The PATH (Prospective Antifungal Therapy) Alliance(R) registry and invasive fungal infections: update 2012. Diagn Microbiol Infect Dis. 2012;73(4):293–300. doi: 10.1016/j.diagmicrobio.2012.06.012.CrossRefPubMedGoogle Scholar
  3. 3.
    Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis. 2004;39(3):309–17. doi: 10.1086/421946CID32752.CrossRefPubMedGoogle Scholar
  4. 4.
    Edmond MB, Wallace SE, McClish DK, Pfaller MA, Jones RN, Wenzel RP. Nosocomial bloodstream infections in United States hospitals: a three-year analysis. Clin Infect Dis. 1999;29(2):239–44. doi: 10.1086/520192.CrossRefPubMedGoogle Scholar
  5. 5.
    Pappas PG, Rex JH, Lee J, Hamill RJ, Larsen RA, Powderly W, et al. A prospective observational study of candidemia: epidemiology, therapy, and influences on mortality in hospitalized adult and pediatric patients. Clin Infect Dis. 2003;37(5):634–43. doi: 10.1086/376906.CrossRefPubMedGoogle Scholar
  6. 6.
    Falagas ME, Apostolou KE, Pappas VD. Attributable mortality of candidemia: a systematic review of matched cohort and case-control studies. Eur J Clin Microbiol Infect Dis. 2006;25(7):419–25. doi: 10.1007/s10096-006-0159-2.CrossRefPubMedGoogle Scholar
  7. 7.
    Andes DR, Safdar N, Baddley JW, Playford G, Reboli AC, Rex JH, et al. Impact of treatment strategy on outcomes in patients with candidemia and other forms of invasive candidiasis: a patient-level quantitative review of randomized trials. Clin Infect Dis. 2012;54(8):1110–22. doi: 10.1093/cid/cis021.CrossRefPubMedGoogle Scholar
  8. 8.
    Khatib R, Johnson LB, Fakih MG, Riederer K, Briski L. Current trends in candidemia and species distribution among adults: Candida glabrata surpasses C. albicans in diabetic patients and abdominal sources. Mycoses. 2016. doi: 10.1111/myc.12531.PubMedGoogle Scholar
  9. 9.
    Lockhart SR, Iqbal N, Cleveland AA, Farley MM, Harrison LH, Bolden CB, et al. Species identification and antifungal susceptibility testing of Candida bloodstream isolates from population-based surveillance studies in two U.S. cities from 2008 to 2011. J Clin Microbiol. 2012;50(11):3435–42. doi: 10.1128/JCM.01283-12.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Lortholary O, Renaudat C, Sitbon K, Madec Y, Denoeud-Ndam L, Wolff M, et al. Worrisome trends in incidence and mortality of candidemia in intensive care units (Paris area, 2002–2010). Intensive Care Med. 2014;40(9):1303–12. doi: 10.1007/s00134-014-3408-3.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Milazzo L, Peri AM, Mazzali C, Grande R, Cazzani C, Ricaboni D, et al. Candidaemia observed at a university hospital in Milan (northern Italy) and review of published studies from 2010 to 2014. Mycopathologia. 2014;178(3-4):227–41. doi: 10.1007/s11046-014-9786-9.CrossRefPubMedGoogle Scholar
  12. 12.
    Borg-von Zepelin M, Kunz L, Ruchel R, Reichard U, Weig M, Gross U. Epidemiology and antifungal susceptibilities of Candida spp. to six antifungal agents: results from a surveillance study on fungaemia in Germany from July 2004 to August 2005. J Antimicrob Chemother. 2007;60(2):424–8. doi: 10.1093/jac/dkm145.CrossRefPubMedGoogle Scholar
  13. 13.
    Matsumoto E, Boyken L, Tendolkar S, McDanel J, Castanheira M, Pfaller M, et al. Candidemia surveillance in Iowa: emergence of echinocandin resistance. Diagn Microbiol Infect Dis. 2014;79(2):205–8. doi: 10.1016/j.diagmicrobio.2014.02.016.CrossRefPubMedGoogle Scholar
  14. 14.
    Tortorano AM, Kibbler C, Peman J, Bernhardt H, Klingspor L, Grillot R. Candidaemia in Europe: epidemiology and resistance. Int J Antimicrob Agents. 2006;27(5):359–66. doi: 10.1016/j.ijantimicag.2006.01.002.CrossRefPubMedGoogle Scholar
  15. 15.
    Trick WE, Fridkin SK, Edwards JR, Hajjeh RA, Gaynes RP. National nosocomial infections surveillance system H. Secular trend of hospital-acquired candidemia among intensive care unit patients in the United States during 1989-1999. Clin Infect Dis. 2002;35(5):627–30. doi: 10.1086/342300.CrossRefPubMedGoogle Scholar
  16. 16.
    Chow JK, Golan Y, Ruthazer R, Karchmer AW, Carmeli Y, Lichtenberg D, et al. Factors associated with candidemia caused by non-albicans Candida species versus Candida albicans in the intensive care unit. Clin Infect Dis. 2008;46(8):1206–13. doi: 10.1086/529435.CrossRefPubMedGoogle Scholar
  17. 17.
    Hachem R, Hanna H, Kontoyiannis D, Jiang Y, Raad I. The changing epidemiology of invasive candidiasis: Candida glabrata and Candida krusei as the leading causes of candidemia in hematologic malignancy. Cancer. 2008;112(11):2493–9. doi: 10.1002/cncr.23466.CrossRefPubMedGoogle Scholar
  18. 18.
    Segireddy M, Johnson LB, Szpunar SM, Khatib R. Differences in patient risk factors and source of candidaemia caused by Candida albicans and Candida glabrata. Mycoses. 2011;54(4):e39–43. doi: 10.1111/j.1439-0507.2009.01824.x.CrossRefPubMedGoogle Scholar
  19. 19.
    Bodey GP, Mardani M, Hanna HA, Boktour M, Abbas J, Girgawy E, et al. The epidemiology of Candida glabrata and Candida albicans fungemia in immunocompromised patients with cancer. Am J Med. 2002;112(5):380–5.CrossRefPubMedGoogle Scholar
  20. 20.
    Imhof A, Balajee SA, Fredricks DN, Englund JA, Marr KA. Breakthrough fungal infections in stem cell transplant recipients receiving voriconazole. Clin Infect Dis. 2004;39(5):743–6. doi: 10.1086/423274.CrossRefPubMedGoogle Scholar
  21. 21.
    Kontoyiannis DP, Reddy BT, Hanna H, Bodey GP, Tarrand J, Raad II. Breakthrough candidemia in patients with cancer differs from de novo candidemia in host factors and Candida species but not intensity. Infect Control Hosp Epidemiol. 2002;23(9):542–5. doi: 10.1086/502104.CrossRefPubMedGoogle Scholar
  22. 22.
    Lee I, Fishman NO, Zaoutis TE, Morales KH, Weiner MG, Synnestvedt M, et al. Risk factors for fluconazole-resistant Candida glabrata bloodstream infections. Arch Intern Med. 2009;169(4):379–83. doi: 10.1001/archinte.169.4.379.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1–50. doi: 10.1093/cid/civ933.CrossRefPubMedGoogle Scholar
  24. 24.
    Khan ZU, Ahmad S, Al-Obaid I, Al-Sweih NA, Joseph L, Farhat D. Emergence of resistance to amphotericin B and triazoles in Candida glabrata vaginal isolates in a case of recurrent vaginitis. J Chemother. 2008;20(4):488–91. doi: 10.1179/joc.2008.20.4.488.CrossRefPubMedGoogle Scholar
  25. 25.
    Chapeland-Leclerc F, Hennequin C, Papon N, Noel T, Girard A, Socie G, et al. Acquisition of flucytosine, azole, and caspofungin resistance in Candida glabrata bloodstream isolates serially obtained from a hematopoietic stem cell transplant recipient. Antimicrob Agents Chemother. 2010;54(3):1360–2. doi: 10.1128/AAC.01138-09.CrossRefPubMedGoogle Scholar
  26. 26.
    Cho EJ, Shin JH, Kim SH, Kim HK, Park JS, Sung H, et al. Emergence of multiple resistance profiles involving azoles, echinocandins and amphotericin B in Candida glabrata isolates from a neutropenia patient with prolonged fungaemia. J Antimicrob Chemother. 2015;70(4):1268–70. doi: 10.1093/jac/dku518.PubMedGoogle Scholar
  27. 27.
    Farmakiotis D, Tarrand JJ, Kontoyiannis DP. Drug-resistant Candida glabrata infection in cancer patients. Emerg Infect Dis. 2014;20(11):1833–40. doi: 10.3201/eid2011.140685.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Hull CM, Parker JE, Bader O, Weig M, Gross U, Warrilow AG, et al. Facultative sterol uptake in an ergosterol-deficient clinical isolate of Candida glabrata harboring a missense mutation in ERG11 and exhibiting cross-resistance to azoles and amphotericin B. Antimicrob Agents Chemother. 2012;56(8):4223–32. doi: 10.1128/AAC.06253-11.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Garnaud C, Botterel F, Sertour N, Bougnoux ME, Dannaoui E, Larrat S, et al. Next-generation sequencing offers new insights into the resistance of Candida spp. to echinocandins and azoles. J Antimicrob Chemother. 2015;70(9):2556–65. doi: 10.1093/jac/dkv139.CrossRefPubMedGoogle Scholar
  30. 30.
    • Miyazaki H, Miyazaki Y, Geber A, Parkinson T, Hitchcock C, Falconer DJ, et al. Fluconazole resistance associated with drug efflux and increased transcription of a drug transporter gene, PDH1, in Candida glabrata. Antimicrob Agents Chemother. 1998;42(7):1695–701. This represents the first indication of a multidrug transporter contributing to fluconazole resistance in C. glabrata. PubMedPubMedCentralGoogle Scholar
  31. 31.
    Izumikawa K, Kakeya H, Tsai HF, Grimberg B, Bennett JE. Function of Candida glabrata ABC transporter gene, PDH1. Yeast. 2003;20(3):249–61. doi: 10.1002/yea.962.CrossRefPubMedGoogle Scholar
  32. 32.
    Sanglard D, Ischer F, Bille J. Role of ATP-binding-cassette transporter genes in high-frequency acquisition of resistance to azole antifungals in Candida glabrata. Antimicrob Agents Chemother. 2001;45(4):1174–83. doi: 10.1128/AAC.45.4.1174-1183.2001.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    •• Sanglard D, Ischer F, Calabrese D, Majcherczyk PA, Bille J. 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. 1999;43(11):2753–65. This paper describes the predominant multidrug transporter involved in fluconazole resistance in C. glabrata. PubMedPubMedCentralGoogle Scholar
  34. 34.
    Vermitsky JP, Edlind TD. Azole resistance in Candida glabrata: coordinate upregulation of multidrug transporters and evidence for a Pdr1-like transcription factor. Antimicrob Agents Chemother. 2004;48(10):3773–81. doi: 10.1128/AAC.48.10.3773-3781.200448/10/3773.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Sanguinetti M, Posteraro B, Fiori B, Ranno S, Torelli R, Fadda G. Mechanisms of azole resistance in clinical isolates of Candida glabrata collected during a hospital survey of antifungal resistance. Antimicrob Agents Chemother. 2005;49(2):668–79. doi: 10.1128/AAC.49.2.668-679.2005.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    • Torelli R, Posteraro B, Ferrari S, La Sorda M, Fadda G, Sanglard D, et al. The ATP-binding cassette transporter-encoding gene CgSNQ2 is contributing to the CgPDR1-dependent azole resistance of Candida glabrata. Mol Microbiol. 2008;68(1):186–201. doi: 10.1111/j.1365-2958.2008.06143.x. This paper demonstrates an important role for a third multidrug transporter in fluconazole resistance in C. glabrata.CrossRefPubMedGoogle Scholar
  37. 37.
    Sanglard D, Kuchler K, Ischer F, Pagani JL, Monod M, Bille J. Mechanisms of resistance to azole antifungal agents in Candida albicans isolates from AIDS patients involve specific multidrug transporters. Antimicrob Agents Chemother. 1995;39(11):2378–86.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Sanglard D, Ischer F, Monod M, Bille J. Susceptibilities of Candida albicans multidrug transporter mutants to various antifungal agents and other metabolic inhibitors. Antimicrob Agents Chemother. 1996;40(10):2300–5.PubMedPubMedCentralGoogle Scholar
  39. 39.
    •• Vermitsky JP, Earhart KD, Smith WL, Homayouni R, Edlind TD, Rogers PD. Pdr1 regulates multidrug resistance in Candida glabrata: gene disruption and genome-wide expression studies. Mol Microbiol. 2006;61(3):704–22. doi: 10.1111/j.1365-2958.2006.05235.x. Along with 44, this paper describes the genetic basis for fluconazole resistance in C. glabrata and delineates the gene regulated by an activating mutation in the gene encoding Pdr1. CrossRefPubMedGoogle Scholar
  40. 40.
    Caudle KE, Barker KS, Wiederhold NP, Xu L, Homayouni R, Rogers PD. Genomewide expression profile analysis of the Candida glabrata Pdr1 regulon. Eukaryot Cell. 2011;10(3):373–83. doi: 10.1128/EC.00073-10.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Costa C, Pires C, Cabrito TR, Renaudin A, Ohno M, Chibana H, et al. Candida glabrata drug:H+ antiporter CgQdr2 confers imidazole drug resistance, being activated by transcription factor CgPdr1. Antimicrob Agents Chemother. 2013;57(7):3159–67. doi: 10.1128/AAC.00811-12.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Paul S, Schmidt JA, Moye-Rowley WS. Regulation of the CgPdr1 transcription factor from the pathogen Candida glabrata. Eukaryot Cell. 2011;10(2):187–97. doi: 10.1128/EC.00277-10.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    • Paul S, Bair TB, Moye-Rowley WS. Identification of genomic binding sites for Candida glabrata Pdr1 transcription factor in wild-type and rho0 cells. Antimicrob Agents Chemother. 2014;58(11):6904–12. doi: 10.1128/AAC.03921-14. This paper delineates the transcriptional targets of Pdr1 when activated by loss of mitochondrial function. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    • Tsai HF, Krol AA, Sarti KE, Bennett JE. Candida glabrata PDR1, a transcriptional regulator of a pleiotropic drug resistance network, mediates azole resistance in clinical isolates and petite mutants. Antimicrob Agents Chemother. 2006;50(4):1384–92. doi: 10.1128/AAC.50.4.1384-1392.2006. Along with 39, this paper describes the genetic basis for fluconazole resistance in C. glabrata. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Tsai HF, Sammons LR, Zhang X, Suffis SD, Su Q, Myers TG, et al. Microarray and molecular analyses of the azole resistance mechanism in Candida glabrata oropharyngeal isolates. Antimicrob Agents Chemother. 2010;54(8):3308–17. doi: 10.1128/AAC.00535-10.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    •• Ferrari S, Ischer F, Calabrese D, Posteraro B, Sanguinetti M, Fadda G, et al. Gain of function mutations in CgPDR1 of Candida glabrata not only mediate antifungal resistance but also enhance virulence. PLoS Pathog. 2009;5(1):e1000268. doi: 10.1371/journal.ppat.1000268. This paper establishes activating mutations in the gene encoding Pdr1 as the primary mechanism of fluconazole resistance and demonstrates that such mutations enhance fitness and virulence.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Bennett JE, Izumikawa K, Marr KA. Mechanism of increased fluconazole resistance in Candida glabrata during prophylaxis. Antimicrob Agents Chemother. 2004;48(5):1773–7.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    • Thakur JK, Arthanari H, Yang F, Pan SJ, Fan X, Breger J, et al. A nuclear receptor-like pathway regulating multidrug resistance in fungi. Nature. 2008;452(7187):604–9. doi: 10.1038/nature06836. This paper suggests a mechanism by which Pdr1 is activated by ketoconazole. CrossRefPubMedGoogle Scholar
  49. 49.
    •• Nishikawa JL, Boeszoermenyi A, Vale-Silva LA, Torelli R, Posteraro B, Sohn YJ, et al. Inhibiting fungal multidrug resistance by disrupting an activator-Mediator interaction. Nature. 2016;530(7591):485–9. doi: 10.1038/nature16963. This paper demonstrates that the Pdr1-Mediator interaction can be chemically disrupted, thereby pointing to the possibility of a co-therapeutic strategy to overcome fluconazole resistance in C. glabrata. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Borah S, Shivarathri R, Kaur R. The Rho1 GTPase-activating protein CgBem2 is required for survival of azole stress in Candida glabrata. J Biol Chem. 2011;286(39):34311–24. doi: 10.1074/jbc.M111.264671.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Borah S, Shivarathri R, Srivastava VK, Ferrari S, Sanglard D, Kaur R. Pivotal role for a tail subunit of the RNA polymerase II mediator complex CgMed2 in azole tolerance and adherence in Candida glabrata. Antimicrob Agents Chemother. 2014;58(10):5976–86. doi: 10.1128/AAC.02786-14.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Akache B, MacPherson S, Sylvain MA, Turcotte B. Complex interplay among regulators of drug resistance genes in Saccharomyces cerevisiae. J Biol Chem. 2004;279(27):27855–60. doi: 10.1074/jbc.M403487200.CrossRefPubMedGoogle Scholar
  53. 53.
    Noble JA, Tsai HF, Suffis SD, Su Q, Myers TG, Bennett JE. STB5 is a negative regulator of azole resistance in Candida glabrata. Antimicrob Agents Chemother. 2013;57(2):959–67. doi: 10.1128/AAC.01278-12.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Ma B, Pan SJ, Domergue R, Rigby T, Whiteway M, Johnson D, et al. High-affinity transporters for NAD+ precursors in Candida glabrata are regulated by Hst1 and induced in response to niacin limitation. Mol Cell Biol. 2009;29(15):4067–79. doi: 10.1128/MCB.01461-08.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Orta-Zavalza E, Guerrero-Serrano G, Gutierrez-Escobedo G, Canas-Villamar I, Juarez-Cepeda J, Castano I, et al. Local silencing controls the oxidative stress response and the multidrug resistance in Candida glabrata. Mol Microbiol. 2013;88(6):1135–48. doi: 10.1111/mmi.12247.CrossRefPubMedGoogle Scholar
  56. 56.
    vanden Bossche H, Marichal P, Odds FC, Le Jeune L, Coene MC. Characterization of an azole-resistant Candida glabrata isolate. Antimicrob Agents Chemother. 1992;36(12):2602–10.CrossRefGoogle Scholar
  57. 57.
    Marichal P, Vanden Bossche H, Odds FC, Nobels G, Warnock DW, Timmerman V, et al. Molecular biological characterization of an azole-resistant Candida glabrata isolate. Antimicrob Agents Chemother. 1997;41(10):2229–37.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Redding SW, Kirkpatrick WR, Saville S, Coco BJ, White W, Fothergill A, et al. Multiple patterns of resistance to fluconazole in Candida glabrata isolates from a patient with oropharyngeal candidiasis receiving head and neck radiation. J Clin Microbiol. 2003;41(2):619–22.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Nagi M, Nakayama H, Tanabe K, Bard M, Aoyama T, Okano M, et al. Transcription factors CgUPC2A and CgUPC2B regulate ergosterol biosynthetic genes in Candida glabrata. Genes Cells. 2011;16(1):80–9. doi: 10.1111/j.1365-2443.2010.01470.x.CrossRefPubMedGoogle Scholar
  60. 60.
    •• Whaley SG, Caudle KE, Vermitsky JP, Chadwick SG, Toner G, Barker KS, et al. UPC2A is required for high-level azole antifungal resistance in Candida glabrata. Antimicrob Agents Chemother. 2014;58(8):4543–54. doi: 10.1128/AAC.02217-13. This paper demonstrates the importance of the sterol biosynthesis regulator Upc2A in fluconzole resistance in C. glabrata and points to a strategy for overcoming it. CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Nakayama H, Izuta M, Nakayama N, Arisawa M, Aoki Y. Depletion of the squalene synthase (ERG9) gene does not impair growth of Candida glabrata in mice. Antimicrob Agents Chemother. 2000;44(9):2411–8.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Tsai HF, Bard M, Izumikawa K, Krol AA, Sturm AM, Culbertson NT, et al. Candida glabrata erg1 mutant with increased sensitivity to azoles and to low oxygen tension. Antimicrob Agents Chemother. 2004;48(7):2483–9. doi: 10.1128/AAC.48.7.2483-2489.2004.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Zavrel M, Hoot SJ, White TC. Comparison of sterol import under aerobic and anaerobic conditions in three fungal species, Candida albicans, Candida glabrata, and Saccharomyces cerevisiae. Eukaryot Cell. 2013;12(5):725–38. doi: 10.1128/EC.00345-12.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Hazen KC, Stei J, Darracott C, Breathnach A, May J, Howell SA. Isolation of cholesterol-dependent Candida glabrata from clinical specimens. Diagn Microbiol Infect Dis. 2005;52(1):35–7. doi: 10.1016/j.diagmicrobio.2004.12.006.CrossRefPubMedGoogle Scholar
  65. 65.
    Bard M, Sturm AM, Pierson CA, Brown S, Rogers KM, Nabinger S, et al. Sterol uptake in Candida glabrata: rescue of sterol auxotrophic strains. Diagn Microbiol Infect Dis. 2005;52(4):285–93. doi: 10.1016/j.diagmicrobio.2005.03.001.CrossRefPubMedGoogle Scholar
  66. 66.
    Nakayama H, Tanabe K, Bard M, Hodgson W, Wu S, Takemori D, et al. The Candida glabrata putative sterol transporter gene CgAUS1 protects cells against azoles in the presence of serum. J Antimicrob Chemother. 2007;60(6):1264–72. doi: 10.1093/jac/dkm321.CrossRefPubMedGoogle Scholar
  67. 67.
    Nagi M, Tanabe K, Ueno K, Nakayama H, Aoyama T, Chibana H, et al. The Candida glabrata sterol scavenging mechanism, mediated by the ATP-binding cassette transporter Aus1p, is regulated by iron limitation. Mol Microbiol. 2013;88(2):371–81. doi: 10.1111/mmi.12189.CrossRefPubMedGoogle Scholar
  68. 68.
    Sasse C, Dunkel N, Schafer T, Schneider S, Dierolf F, Ohlsen K, et al. The stepwise acquisition of fluconazole resistance mutations causes a gradual loss of fitness in Candida albicans. Mol Microbiol. 2012;86(3):539–56. doi: 10.1111/j.1365-2958.2012.08210.x.CrossRefPubMedGoogle Scholar
  69. 69.
    • Vale-Silva L, Ischer F, Leibundgut-Landmann S, Sanglard D. Gain-of-function mutations in PDR1, a regulator of antifungal drug resistance in Candida glabrata, control adherence to host cells. Infect Immun. 2013;81(5):1709–20. doi: 10.1128/IAI.00074-13. This paper further establishes the contribution of activating mutations in Pdr1 to virulence through increased adherence to host cells.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    • Vale-Silva LA, Moeckli B, Torelli R, Posteraro B, Sanguinetti M, Sanglard D. Upregulation of the adhesin gene EPA1 mediated by PDR1 in Candida glabrata leads to enhanced host colonization. mSphere. 2016;1(2). doi: 10.1128/mSphere.00065-15. This paper demonstrates a role for Pdr1-mediated EPA1 expression in enhanced host colonization.
  71. 71.
    Ferrari S, Sanguinetti M, Torelli R, Posteraro B, Sanglard D. Contribution of CgPDR1-regulated genes in enhanced virulence of azole-resistant Candida glabrata. PLoS One. 2011;6(3):e17589. doi: 10.1371/journal.pone.0017589.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Devaux F, Carvajal E, Moye-Rowley S, Jacq C. Genome-wide studies on the nuclear PDR3-controlled response to mitochondrial dysfunction in yeast. FEBS Lett. 2002;515(1-3):25–8.CrossRefPubMedGoogle Scholar
  73. 73.
    Hallstrom TC, Moye-Rowley WS. Multiple signals from dysfunctional mitochondria activate the pleiotropic drug resistance pathway in Saccharomyces cerevisiae. J Biol Chem. 2000;275(48):37347–56. doi: 10.1074/jbc.M007338200.CrossRefPubMedGoogle Scholar
  74. 74.
    Defontaine A, Bouchara JP, Declerk P, Planchenault C, Chabasse D, Hallet JN. In-vitro resistance to azoles associated with mitochondrial DNA deficiency in Candida glabrata. J Med Microbiol. 1999;48(7):663–70. doi: 10.1099/00222615-48-7-663.CrossRefPubMedGoogle Scholar
  75. 75.
    Brun S, Berges T, Poupard P, Vauzelle-Moreau C, Renier G, Chabasse D, et al. Mechanisms of azole resistance in petite mutants of Candida glabrata. Antimicrob Agents Chemother. 2004;48(5):1788–96.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Ferrari S, Sanguinetti M, De Bernardis F, Torelli R, Posteraro B, Vandeputte P, et al. Loss of mitochondrial functions associated with azole resistance in Candida glabrata results in enhanced virulence in mice. Antimicrob Agents Chemother. 2011;55(5):1852–60. doi: 10.1128/AAC.01271-10.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Brun S, Dalle F, Saulnier P, Renier G, Bonnin A, Chabasse D, et al. Biological consequences of petite mutations in Candida glabrata. J Antimicrob Chemother. 2005;56(2):307–14. doi: 10.1093/jac/dki200.CrossRefPubMedGoogle Scholar
  78. 78.
    Bouchara JP, Zouhair R, Le Boudouil S, Renier G, Filmon R, Chabasse D, et al. In-vivo selection of an azole-resistant petite mutant of Candida glabrata. J Med Microbiol. 2000;49(11):977–84. doi: 10.1099/0022-1317-49-11-977.CrossRefPubMedGoogle Scholar
  79. 79.
    Peng Y, Dong D, Jiang C, Yu B, Wang X, Ji Y. Relationship between respiration deficiency and azole resistance in clinical Candida glabrata. FEMS Yeast Res. 2012;12(6):719–27. doi: 10.1111/j.1567-1364.2012.00821.x.CrossRefPubMedGoogle Scholar
  80. 80.
    •• Healey KR, Zhao Y, Perez WB, Lockhart SR, Sobel JD, Farmakiotis D, et al. Prevalent mutator genotype identified in fungal pathogen Candida glabrata promotes multi-drug resistance. Nat Commun. 2016;7:11128. doi: 10.1038/ncomms11128. This work establishes a mechanism by which C. glabrata rapidly develops antifungal resistance. CrossRefPubMedGoogle Scholar
  81. 81.
    Shin JH, Chae MJ, Song JW, Jung SI, Cho D, Kee SJ, et al. Changes in karyotype and azole susceptibility of sequential bloodstream isolates from patients with Candida glabrata candidemia. J Clin Microbiol. 2007;45(8):2385–91. doi: 10.1128/JCM.00381-07.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Klempp-Selb B, Rimek D, Kappe R. Karyotyping of Candida albicans and Candida glabrata from patients with Candida sepsis. Mycoses. 2000;43(5):159–63.CrossRefPubMedGoogle Scholar
  83. 83.
    Selmecki A, Forche A, Berman J. Aneuploidy and isochromosome formation in drug-resistant Candida albicans. Science. 2006;313(5785):367–70. doi: 10.1126/science.1128242.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Polakova S, Blume C, Zarate JA, Mentel M, Jorck-Ramberg D, Stenderup J, et al. Formation of new chromosomes as a virulence mechanism in yeast Candida glabrata. Proc Natl Acad Sci U S A. 2009;106(8):2688–93. doi: 10.1073/pnas.0809793106.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Ahmad KM, Ishchuk OP, Hellborg L, Jorgensen G, Skvarc M, Stenderup J, et al. Small chromosomes among Danish Candida glabrata isolates originated through different mechanisms. Antonie Van Leeuwenhoek. 2013;104(1):111–22. doi: 10.1007/s10482-013-9931-3.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    El-Halfawy OM, Valvano MA. Antimicrobial heteroresistance: an emerging field in need of clarity. Clin Microbiol Rev. 2015;28(1):191–207. doi: 10.1128/CMR.00058-14.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    •• Ben-Ami R, Zimmerman O, Finn T, Amit S, Novikov A, Wertheimer N, et al. Heteroresistance to fluconazole is a continuously distributed phenotype among Candida glabrata clinical strains associated with in vivo persistence. MBio. 2016;7(4):e00655–16. doi: 10.1128/mBio.00655-16. This work establishes the importance of heteroresistance in fluconazole resistance among clinical isolates of C. glabrata. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of Clinical Pharmacy, Center for Pediatric Pharmacokinetics and Therapeutics, College of PharmacyUniversity of Tennessee Health Science CenterMemphisUSA

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