Systematic Phenotyping of a Large-Scale Deletion Collection Reveals Novel Antifungal Tolerance Genes

1. MeanM, MarchettiO, CalandraT (2008) Bench-to-bedside review: Candida infections in the intensive care unit. Crit Care 12: 204.

2. PerlrothJ, ChoiB, SpellbergB (2007) Nosocomial fungal infections: epidemiology, diagnosis, and treatment. Med Mycol 45: 321–346.

3. PfallerMA, DiekemaDJ, GibbsDL, NewellVA, BartonR, et al. (2010) Geographic variation in the frequency of isolation and fluconazole and voriconazole susceptibilities of Candida glabrata: an assessment from the ARTEMIS DISK Global Antifungal Surveillance Program. Diagn Microbiol Infect Dis 67: 162–171.

4. RichardsonM, Lass-FlorlC (2008) Changing epidemiology of systemic fungal infections. Clin Microbiol Infect 14 Suppl 4: 5–24.

5. GowNA, van de VeerdonkFL, BrownAJ, NeteaMG (2011) Candida albicans morphogenesis and host defence: discriminating invasion from colonization. Nat Rev Microbiol 10: 112–122.

6. AlbrechtA, FelkA, PichovaI, NaglikJR, SchallerM, et al. (2006) Glycosylphosphatidylinositol-anchored proteases of Candida albicans target proteins necessary for both cellular processes and host-pathogen interactions. J Biol Chem 281: 688–694.

7. GhannoumMA (2000) Potential role of phospholipases in virulence and fungal pathogenesis. Clin Microbiol Rev 13: 122–143 table of contents.

8. PanackalAA, GribskovJL, StaabJF, KirbyKA, RinaldiM, et al. (2006) Clinical significance of azole antifungal drug cross-resistance in Candida glabrata. J Clin Microbiol 44: 1740–1743.

9. PfallerMA, DiekemaDJ, GibbsDL, NewellVA, EllisD, et al. (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: 1366–1377.

10. PfallerMA, MesserSA, HollisRJ, BoykenL, TendolkarS, et al. (2009) Variation in susceptibility of bloodstream isolates of Candida glabrata to fluconazole according to patient age and geographic location in the United States in 2001 to 2007. J Clin Microbiol 47: 3185–3190.

11. RuanSY, ChuCC, HsuehPR (2008) In vitro susceptibilities of invasive isolates of Candida species: rapid increase in rates of fluconazole susceptible-dose dependent Candida glabrata isolates. Antimicrob Agents Chemother 52: 2919–2922.

12. CastanoI, PanSJ, ZupancicM, HennequinC, DujonB, et al. (2005) Telomere length control and transcriptional regulation of subtelomeric adhesins in Candida glabrata. Mol Microbiol 55: 1246–1258.

13. CormackBP, GhoriN, FalkowS (1999) An adhesin of the yeast pathogen Candida glabrata mediating adherence to human epithelial cells. Science 285: 578–582.

14. de GrootPW, KraneveldEA, YinQY, DekkerHL, GrossU, et al. (2008) The cell wall of the human pathogen Candida glabrata: differential incorporation of novel adhesin-like wall proteins. Eukaryot Cell 7: 1951–1964.

15. De Las PenasA, PanSJ, CastanoI, AlderJ, CreggR, et al. (2003) Virulence-related surface glycoproteins in the yeast pathogen Candida glabrata are encoded in subtelomeric clusters and subject to RAP1- and SIR-dependent transcriptional silencing. Genes Dev 17: 2245–2258.

16. DomergueR, CastanoI, De Las PenasA, ZupancicM, LockatellV, et al. (2005) Nicotinic acid limitation regulates silencing of Candida adhesins during UTI. Science 308: 866–870.

17. KaurR, DomergueR, ZupancicML, CormackBP (2005) A yeast by any other name: Candida glabrata and its interaction with the host. Curr Opin Microbiol 8: 378–384.

18. KaurR, MaB, CormackBP (2007) A family of glycosylphosphatidylinositol-linked aspartyl proteases is required for virulence of Candida glabrata. Proc Natl Acad Sci U S A 104: 7628–7633.

19. BrunkeS, SeiderK, AlmeidaRS, HeykenA, FleckCB, et al. (2010) Candida glabrata tryptophan-based pigment production via the Ehrlich pathway. Mol Microbiol 76: 25–47.

20. RoetzerA, GratzN, KovarikP, SchullerC (2010) Autophagy supports Candida glabrata survival during phagocytosis. Cell Microbiol 12: 199–216.

21. SeiderK, BrunkeS, SchildL, JablonowskiN, WilsonD, et al. (2011) The facultative intracellular pathogen Candida glabrata subverts macrophage cytokine production and phagolysosome maturation. J Immunol 187: 3072–3086.

22. RaiMN, BalusuS, GorityalaN, DanduL, KaurR (2012) Functional genomic analysis of Candida glabrata-macrophage interaction: role of chromatin remodeling in virulence. PLoS Pathog 8: e1002863.

23. KamranM, CalcagnoAM, FindonH, BignellE, JonesMD, et al. (2004) Inactivation of transcription factor gene ACE2 in the fungal pathogen Candida glabrata results in hypervirulence. Eukaryot Cell 3: 546–552.

24. IzumikawaK, KakeyaH, TsaiHF, GrimbergB, BennettJE (2003) Function of Candida glabrata ABC transporter gene, PDH1. Yeast 20: 249–261.

25. MiyazakiH, MiyazakiY, GeberA, ParkinsonT, HitchcockC, et al. (1998) Fluconazole resistance associated with drug efflux and increased transcription of a drug transporter gene, PDH1, in Candida glabrata. Antimicrob Agents Chemother 42: 1695–1701.

26. SanglardD, IscherF, CalabreseD, MajcherczykPA, BilleJ (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: 2753–2765.

27. ThakurJK, ArthanariH, YangF, PanSJ, FanX, et al. (2008) A nuclear receptor-like pathway regulating multidrug resistance in fungi. Nature 452: 604–609.

28. VermitskyJP, EarhartKD, SmithWL, HomayouniR, EdlindTD, et al. (2006) Pdr1 regulates multidrug resistance in Candida glabrata: gene disruption and genome-wide expression studies. Mol Microbiol 61: 704–722.

29. BrunS, BergesT, PoupardP, Vauzelle-MoreauC, RenierG, et al. (2004) Mechanisms of azole resistance in petite mutants of Candida glabrata. Antimicrob Agents Chemother 48: 1788–1796.

30. NakayamaH, TanabeK, BardM, HodgsonW, WuS, et al. (2007) The Candida glabrata putative sterol transporter gene CgAUS1 protects cells against azoles in the presence of serum. J Antimicrob Chemother 60: 1264–1272.

31. NagiM, TanabeK, UenoK, NakayamaH, AoyamaT, et al. (2013) The Candida glabrata sterol scavenging mechanism, mediated by the ATP-binding cassette transporter Aus1p, is regulated by iron limitation. Mol Microbiol 88: 371–381.

32. MiyazakiT, YamauchiS, InamineT, NagayoshiY, SaijoT, et al. (2010) Roles of calcineurin and Crz1 in antifungal susceptibility and virulence of Candida glabrata. Antimicrob Agents Chemother 54: 1639–1643.

33. DiekemaD, ArbefevilleS, BoykenL, KroegerJ, PfallerM (2012) The changing epidemiology of healthcare-associated candidemia over three decades. Diagn Microbiol Infect Dis 73: 45–48.

34. PerlinDS (2011) Current perspectives on echinocandin class drugs. Future Microbiol 6: 441–457.

35. PerlinDS (2007) Resistance to echinocandin-class antifungal drugs. Drug Resist Updat 10: 121–130.

36. Singh-BabakSD, BabakT, DiezmannS, HillJA, XieJL, et al. (2012) Global analysis of the evolution and mechanism of echinocandin resistance in Candida glabrata. PLoS Pathog 8: e1002718.

37. KatiyarSK, Alastruey-IzquierdoA, HealeyKR, JohnsonME, PerlinDS, et al. (2012) Fks1 and Fks2 are functionally redundant but differentially regulated in Candida glabrata: implications for echinocandin resistance. Antimicrob Agents Chemother 56: 6304–6309.

38. Schuetzer-MuehlbauerM, WillingerB, KrapfG, EnzingerS, PresterlE, et al. (2003) The Candida albicans Cdr2p ATP-binding cassette (ABC) transporter confers resistance to caspofungin. Mol Microbiol 48: 225–235.

39. SinghSD, RobbinsN, ZaasAK, SchellWA, PerfectJR, et al. (2009) Hsp90 governs echinocandin resistance in the pathogenic yeast Candida albicans via calcineurin. PLoS Pathog 5: e1000532.

40. AlexanderBD, JohnsonMD, PfeifferCD, Jimenez-OrtigosaC, CataniaJ, et al. (2013) Increasing Echinocandin Resistance in Candida glabrata: Clinical Failure Correlates With Presence of FKS Mutations and Elevated Minimum Inhibitory Concentrations. Clin Infect Dis 56: 1724–1732.

41. AlexanderBD, JohnsonMD, PfeifferCD, Jimenez-OrtigosaC, CataniaJ, et al. (2013) Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations. Clin Infect Dis 56: 1724–1732.

42. CostanzoM, BaryshnikovaA, BellayJ, KimY, SpearED, et al. (2010) The genetic landscape of a cell. Science 327: 425–431.

43. GiaeverG, ChuAM, NiL, ConnellyC, RilesL, et al. (2002) Functional profiling of the Saccharomyces cerevisiae genome. Nature 418: 387–391.

44. HillenmeyerME, EricsonE, DavisRW, NislowC, KollerD, et al. (2010) Systematic analysis of genome-wide fitness data in yeast reveals novel gene function and drug action. Genome Biol 11: R30.

45. HillenmeyerME, FungE, WildenhainJ, PierceSE, HoonS, et al. (2008) The chemical genomic portrait of yeast: uncovering a phenotype for all genes. Science 320: 362–365.

46. ParsonsAB, BrostRL, DingH, LiZ, ZhangC, et al. (2004) Integration of chemical-genetic and genetic interaction data links bioactive compounds to cellular target pathways. Nat Biotechnol 22: 62–69.

47. RyanO, ShapiroRS, KuratCF, MayhewD, BaryshnikovaA, et al. (2012) Global gene deletion analysis exploring yeast filamentous growth. Science 337: 1353–1356.

48. TongAH, LesageG, BaderGD, DingH, XuH, et al. (2004) Global mapping of the yeast genetic interaction network. Science 303: 808–813.

49. WinzelerEA, ShoemakerDD, AstromoffA, LiangH, AndersonK, et al. (1999) Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis. Science 285: 901–906.

50. NobleSM, FrenchS, KohnLA, ChenV, JohnsonAD (2010) Systematic screens of a Candida albicans homozygous deletion library decouple morphogenetic switching and pathogenicity. Nat Genet 42: 590–598.

51. NobleSM, JohnsonAD (2005) Strains and strategies for large-scale gene deletion studies of the diploid human fungal pathogen Candida albicans. Eukaryot Cell 4: 298–309.

52. RoemerT, JiangB, DavisonJ, KetelaT, VeilletteK, et al. (2003) Large-scale essential gene identification in Candida albicans and applications to antifungal drug discovery. Mol Microbiol 50: 167–181.

53. LiuOW, ChunCD, ChowED, ChenC, MadhaniHD, et al. (2008) Systematic genetic analysis of virulence in the human fungal pathogen Cryptococcus neoformans. Cell 135: 174–188.

54. DujonB, ShermanD, FischerG, DurrensP, CasaregolaS, et al. (2004) Genome evolution in yeasts. Nature 430: 35–44.

55. Marcet-HoubenM, GabaldonT (2009) The tree versus the forest: the fungal tree of life and the topological diversity within the yeast phylome. PLoS ONE 4: e4357.

56. ReussO, VikA, KolterR, MorschhäuserJ (2004) The SAT1 flipper, an optimized tool for gene disruption in Candida albicans. Gene 341: 119–127.

57. ShenJ, GuoW, KöhlerJR (2005) CaNAT1, a heterologous dominant selectable marker for transformation of Candida albicans and other pathogenic Candida species. Infect Immun 73: 1239–1242.

58. BrandA, MacCallumDM, BrownAJ, GowNA, OddsFC (2004) Ectopic expression of URA3 can influence the virulence phenotypes and proteome of Candida albicans but can be overcome by targeted reintegration of URA3 at the RPS10 locus. Eukaryot Cell 3: 900–909.

59. LayJ, HenryLK, CliffordJ, KoltinY, BulawaCE, et al. (1998) Altered expression of selectable marker URA3 in gene-disrupted Candida albicans strains complicates interpretation of virulence studies. Infect Immun 66: 5301–5306.

60. JacobsenID, BrunkeS, SeiderK, SchwarzmullerT, FironA, et al. (2010) Candida glabrata persistence in mice does not depend on host immunosuppression and is unaffected by fungal amino acid auxotrophy. Infect Immun 78: 1066–1077.

61. UenoK, UnoJ, NakayamaH, SasamotoK, MikamiY, et al. (2007) Development of a highly efficient gene targeting system induced by transient repression of YKU80 expression in Candida glabrata. Eukaryot Cell 6: 1239–1247.

62. BoguslawskiG (1992) PBS2, a yeast gene encoding a putative protein kinase, interacts with the RAS2 pathway and affects osmotic sensitivity of Saccharomyces cerevisiae. J Gen Microbiol 138: 2425–2432.

63. SanglardD, IscherF, BilleJ (2001) Role of ATP-binding-cassette transporter genes in high-frequency acquisition of resistance to azole antifungals in Candida glabrata. Antimicrob Agents Chemother 45: 1174–1183.

64. VermitskyJP, EdlindTD (2004) Azole resistance in Candida glabrata: coordinate upregulation of multidrug transporters and evidence for a Pdr1-like transcription factor. Antimicrob Agents Chemother 48: 3773–3781.

65. CotaJM, GrabinskiJL, TalbertRL, BurgessDS, RogersPD, et al. (2008) Increases in SLT2 expression and chitin content are associated with incomplete killing of Candida glabrata by caspofungin. Antimicrob Agents Chemother 52: 1144–1146.

66. Reinoso-MartinC, SchullerC, Schuetzer-MuehlbauerM, KuchlerK (2003) The yeast protein kinase C cell integrity pathway mediates tolerance to the antifungal drug caspofungin through activation of Slt2p mitogen-activated protein kinase signaling. Eukaryot Cell 2: 1200–1210.

67. FerrariS, IscherF, CalabreseD, PosteraroB, SanguinettiM, et al. (2009) Gain of function mutations in CgPDR1 of Candida glabrata not only mediate antifungal resistance but also enhance virulence. PLoS Pathog 5: e1000268.

68. St OngeRP, ManiR, OhJ, ProctorM, FungE, et al. (2007) Systematic pathway analysis using high-resolution fitness profiling of combinatorial gene deletions. Nat Genet 39: 199–206.

69. CsankC, HaynesK (2000) Candida glabrata displays pseudohyphal growth. FEMS Microbiol Lett 189: 115–120.

70. VandeputteP, TronchinG, BergesT, HennequinC, ChabasseD, et al. (2007) Reduced susceptibility to polyenes associated with a missense mutation in the ERG6 gene in a clinical isolate of Candida glabrata with pseudohyphal growth. Antimicrob Agents Chemother 51: 982–990.

71. FinkelJS, MitchellAP (2011) Genetic control of Candida albicans biofilm development. Nat Rev Microbiol 9: 109–118.

72. NobileCJ, NettJE, HerndayAD, HomannOR, DeneaultJS, et al. (2009) Biofilm matrix regulation by Candida albicans Zap1. PLoS Biol 7: e1000133.

73. RieraM, MogensenE, d'EnfertC, JanbonG (2012) New regulators of biofilm development in Candida glabrata. Res Microbiol 163: 297–307.

74. HonraetK, GoetghebeurE, NelisHJ (2005) Comparison of three assays for the quantification of Candida biomass in suspension and CDC reactor grown biofilms. J Microbiol Methods 63: 287–295.

75. IraquiI, Garcia-SanchezS, AubertS, DromerF, GhigoJM, et al. (2005) The Yak1p kinase controls expression of adhesins and biofilm formation in Candida glabrata in a Sir4p-dependent pathway. Mol Microbiol 55: 1259–1271.

76. PfallerMA, CastanheiraM, LockhartSR, AhlquistAM, MesserSA, et al. (2012) Frequency of decreased susceptibility and resistance to echinocandins among fluconazole-resistant bloodstream isolates of Candida glabrata. J Clin Microbiol 50: 1199–1203.

77. CowenLE (2008) The evolution of fungal drug resistance: modulating the trajectory from genotype to phenotype. Nat Rev Microbiol 6: 187–198.

78. KhanZU, AhmadS, Al-ObaidI, Al-SweihNA, JosephL, et al. (2008) Emergence of resistance to amphotericin B and triazoles in Candida glabrata vaginal isolates in a case of recurrent vaginitis. J Chemother 20: 488–491.

79. Krogh-MadsenM, ArendrupMC, HesletL, KnudsenJD (2006) Amphotericin B and caspofungin resistance in Candida glabrata isolates recovered from a critically ill patient. Clin Infect Dis 42: 938–944.

80. LussierM, SdicuAM, CamirandA, BusseyH (1996) Functional characterization of the YUR1, KTR1, and KTR2 genes as members of the yeast KRE2/MNT1 mannosyltransferase gene family. J Biol Chem 271: 11001–11008.

81. OnyewuC, BlankenshipJR, Del PoetaM, HeitmanJ (2003) Ergosterol biosynthesis inhibitors become fungicidal when combined with calcineurin inhibitors against Candida albicans, Candida glabrata, and Candida krusei. Antimicrob Agents Chemother 47: 956–964.

82. TschernerM, StapplerE, HniszD, KuchlerK The histone acetyltransferase Hat1 facilitates DNA damage repair and morphogenesis in Candida albicans. Mol Microbiol

83. MiyazakiT, InamineT, YamauchiS, NagayoshiY, SaijoT, et al. (2010) Role of the Slt2 mitogen-activated protein kinase pathway in cell wall integrity and virulence in Candida glabrata. FEMS Yeast Res 10: 343–352.

84. ChenYL, KonieczkaJH, SpringerDJ, BowenSE, ZhangJ, et al. (2012) Convergent Evolution of Calcineurin Pathway Roles in Thermotolerance and Virulence in Candida glabrata. G3 (Bethesda) 2: 675–691.

85. LiuW, TanJ, SunJ, XuZ, LiM, et al. (2014) Invasive candidiasis in intensive care units in China: in vitro antifungal susceptibility in the China-SCAN study. J Antimicrob Chemother 69: 162–167.

86. CastanoI, KaurR, PanS, CreggR, PenasAdeL, et al. (2003) Tn7-based genome-wide random insertional mutagenesis of Candida glabrata. Genome Res 13: 905–915.

87. KojicEM, DarouicheRO (2004) Candida infections of medical devices. Clin Microbiol Rev 17: 255–267.

88. FriedelAM, PikeBL, GasserSM (2009) ATR/Mec1: coordinating fork stability and repair. Curr Opin Cell Biol 21: 237–244.

89. JorgensenP, NelsonB, RobinsonMD, ChenY, AndrewsB, et al. (2002) High-resolution genetic mapping with ordered arrays of Saccharomyces cerevisiae deletion mutants. Genetics 162: 1091–1099.

90. BidlingmaierS, WeissEL, SeidelC, DrubinDG, SnyderM (2001) The Cbk1p pathway is important for polarized cell growth and cell separation in Saccharomyces cerevisiae. Mol Cell Biol 21: 2449–2462.

91. RackiWJ, BecamAM, NasrF, HerbertCJ (2000) Cbk1p, a protein similar to the human myotonic dystrophy kinase, is essential for normal morphogenesis in Saccharomyces cerevisiae. EMBO J 19: 4524–4532.

92. BharuchaN, Chabrier-RoselloY, XuT, JohnsonC, SobczynskiS, et al. (2011) A large-scale complex haploinsufficiency-based genetic interaction screen in Candida albicans: analysis of the RAM network during morphogenesis. PLoS Genet 7: e1002058.

93. McNemarMD, FonziWA (2002) Conserved serine/threonine kinase encoded by CBK1 regulates expression of several hypha-associated transcripts and genes encoding cell wall proteins in Candida albicans. J Bacteriol 184: 2058–2061.

94. LegrandM, LephartP, ForcheA, MuellerFM, WalshT, et al. (2004) Homozygosity at the MTL locus in clinical strains of Candida albicans: karyotypic rearrangements and tetraploid formation. Mol Microbiol 52: 1451–1462.

95. Gutierrez-EscribanoP, ZeidlerU, SuarezMB, Bachellier-BassiS, Clemente-BlancoA, et al. (2012) The NDR/LATS kinase Cbk1 controls the activity of the transcriptional regulator Bcr1 during biofilm formation in Candida albicans. PLoS Pathog 8: e1002683.

96. LavoieH, HoguesH, WhitewayM (2009) Rearrangements of the transcriptional regulatory networks of metabolic pathways in fungi. Curr Opin Microbiol 12: 655–663.

97. LiH, JohnsonAD (2010) Evolution of transcription networks–lessons from yeasts. Curr Biol 20: R746–753.

98. CasadevallA (2012) Fungi and the rise of mammals. PLoS Pathog 8: e1002808.

99. BennettJE, IzumikawaK, MarrKA (2004) Mechanism of increased fluconazole resistance in Candida glabrata during prophylaxis. Antimicrob Agents Chemother 48: 1773–1777.

100. BorstA, RaimerMT, WarnockDW, MorrisonCJ, Arthington-SkaggsBA (2005) Rapid acquisition of stable azole resistance by Candida glabrata isolates obtained before the clinical introduction of fluconazole. Antimicrob Agents Chemother 49: 783–787.

101. BoucharaJP, ZouhairR, Le BoudouilS, RenierG, FilmonR, et al. (2000) In-vivo selection of an azole-resistant petite mutant of Candida glabrata. J Med Microbiol 49: 977–984.

102. CostaC, PiresC, CabritoTR, RenaudinA, OhnoM, et al. (2013) Candida glabrata drug:H+ antiporter CgQdr2 (ORF CAGL0G08624g) confers imidazole drug resistance, being activated by the CgPdr1 transcription factor. Antimicrob Agents Chemother 57: 3159–3167.

103. MorschhäuserJ, BarkerKS, LiuTT, BlaBWJ, HomayouniR, et al. (2007) The transcription factor Mrr1p controls expression of the MDR1 efflux pump and mediates multidrug resistance in Candida albicans. PLoS Pathog 3: e164.

104. LesageG, SdicuAM, MenardP, ShapiroJ, HusseinS, et al. (2004) Analysis of beta-1,3-glucan assembly in Saccharomyces cerevisiae using a synthetic interaction network and altered sensitivity to caspofungin. Genetics 167: 35–49.

105. XuD, JiangB, KetelaT, LemieuxS, VeilletteK, et al. (2007) Genome-wide fitness test and mechanism-of-action studies of inhibitory compounds in Candida albicans. PLoS Pathog 3: e92.

106. Ben-AmiR, KontoyiannisDP (2012) Resistance to echinocandins comes at a cost: the impact of FKS1 hotspot mutations on Candida albicans fitness and virulence. Virulence 3: 95–97.

107. SussmanA, HussK, ChioLC, HeidlerS, ShawM, et al. (2004) Discovery of cercosporamide, a known antifungal natural product, as a selective Pkc1 kinase inhibitor through high-throughput screening. Eukaryot Cell 3: 932–943.

108. LeeKK, MaccallumDM, JacobsenMD, WalkerLA, OddsFC, et al. (2012) Elevated cell wall chitin in Candida albicans confers echinocandin resistance in vivo. Antimicrob Agents Chemother 56: 208–217.

109. WalkerLA, GowNA, MunroCA (2013) Elevated chitin content reduces the susceptibility of Candida species to caspofungin. Antimicrob Agents Chemother 57: 146–154.

110. SteinbachWJ, CramerRAJr, PerfectBZ, HennC, NielsenK, et al. (2007) Calcineurin inhibition or mutation enhances cell wall inhibitors against Aspergillus fumigatus. Antimicrob Agents Chemother 51: 2979–2981.

111. RoelantsFM, BreslowDK, MuirA, WeissmanJS, ThornerJ (2011) Protein kinase Ypk1 phosphorylates regulatory proteins Orm1 and Orm2 to control sphingolipid homeostasis in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 108: 19222–19227.

112. InagakiM, SchmelzleT, YamaguchiK, IrieK, HallMN, et al. (1999) PDK1 homologs activate the Pkc1-mitogen-activated protein kinase pathway in yeast. Mol Cell Biol 19: 8344–8352.

113. RoelantsFM, TorrancePD, BezmanN, ThornerJ (2002) Pkh1 and Pkh2 differentially phosphorylate and activate Ypk1 and Ykr2 and define protein kinase modules required for maintenance of cell wall integrity. Mol Biol Cell 13: 3005–3028.

114. KaurR, CastanoI, CormackBP (2004) Functional genomic analysis of fluconazole susceptibility in the pathogenic yeast Candida glabrata: roles of calcium signaling and mitochondria. Antimicrob Agents Chemother 48: 1600–1613.

115. WiederholdNP, KontoyiannisDP, PrinceRA, LewisRE (2005) Attenuation of the activity of caspofungin at high concentrations against Candida albicans: possible role of cell wall integrity and calcineurin pathways. Antimicrob Agents Chemother 49: 5146–5148.

116. JansenJM, WanlessAG, SeidelCW, WeissEL (2009) Cbk1 regulation of the RNA-binding protein Ssd1 integrates cell fate with translational control. Curr Biol 19: 2114–2120.

117. GankKD, YeamanMR, KojimaS, YountNY, ParkH, et al. (2008) SSD1 is integral to host defense peptide resistance in Candida albicans. Eukaryot Cell 7: 1318–1327.

118. Colman-LernerA, ChinTE, BrentR (2001) Yeast Cbk1 and Mob2 activate daughter-specific genetic programs to induce asymmetric cell fates. Cell 107: 739–750.

119. KaeberleinM, GuarenteL (2002) Saccharomyces cerevisiae MPT5 and SSD1 function in parallel pathways to promote cell wall integrity. Genetics 160: 83–95.

120. KurischkoC, KuraviVK, HerbertCJ, LucaFC (2011) Nucleocytoplasmic shuttling of Ssd1 defines the destiny of its bound mRNAs. Mol Microbiol 81: 831–849.

121. SunY, TaniguchiR, TanoueD, YamajiT, TakematsuH, et al. (2000) Sli2 (Ypk1), a homologue of mammalian protein kinase SGK, is a downstream kinase in the sphingolipid-mediated signaling pathway of yeast. Mol Cell Biol 20: 4411–4419.

122. RoelantsFM, BaltzAG, TrottAE, FereresS, ThornerJ (2010) A protein kinase network regulates the function of aminophospholipid flippases. Proc Natl Acad Sci U S A 107: 34–39.

123. ParksLW, SmithSJ, CrowleyJH (1995) Biochemical and physiological effects of sterol alterations in yeast–a review. Lipids 30: 227–230.

124. LampingE, LucklJ, PaltaufF, HenrySA, KohlweinSD (1994) Isolation and characterization of a mutant of Saccharomyces cerevisiae with pleiotropic deficiencies in transcriptional activation and repression. Genetics 137: 55–65.

125. PfallerM, NeofytosD, DiekemaD, AzieN, Meier-KriescheHU, et al. (2012) Epidemiology and outcomes of candidemia in 3648 patients: data from the Prospective Antifungal Therapy (PATH Alliance(R)) registry, 2004–2008. Diagn Microbiol Infect Dis 74: 323–331.

126. MorschhauserJ (2010) Regulation of multidrug resistance in pathogenic fungi. Fungal Genet Biol 47: 94–106.

127. Kaiser C, Michaelis S, Mitchell AP (1994) Methods in yeast genetics. A laboratory course manual. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.

128. GabaldonT (2008) Large-scale assignment of orthology: back to phylogenetics? Genome Biol 9: 235.

129. Huerta-CepasJ, Capella-GutierrezS, PryszczLP, DenisovI, KormesD, et al. (2011) PhylomeDB v3.0: an expanding repository of genome-wide collections of trees, alignments and phylogeny-based orthology and paralogy predictions. Nucleic Acids Res 39: D556–560.

130. RiceP, LongdenI, BleasbyA (2000) EMBOSS: the European Molecular Biology Open Software Suite. Trends Genet 16: 276–277.

131. CabralV, ChauvelM, FironA, LegrandM, NesseirA, et al. (2012) Modular gene over-expression strategies for Candida albicans. Methods Mol Biol 845: 227–244.

132. ChauvelM, NesseirA, CabralV, ZnaidiS, GoyardS, et al. (2012) A versatile overexpression strategy in the pathogenic yeast Candida albicans: identification of regulators of morphogenesis and fitness. PLoS One 7: e45912.

133. KitadaK, YamaguchiE, ArisawaM (1996) Isolation of a Candida glabrata centromere and its use in construction of plasmid vectors. Gene 175: 105–108.

134. CormackBP, FalkowS (1999) Efficient homologous and illegitimate recombination in the opportunistic yeast pathogen Candida glabrata. Genetics 151: 979–987.

135. RexJH, PfallerMA, GalgianiJN, BartlettMS, Espinel-IngroffA, et al. (1997) Development of interpretive breakpoints for antifungal susceptibility testing: conceptual framework and analysis of in vitro-in vivo correlation data for fluconazole, itraconazole, and candida infections. Subcommittee on Antifungal Susceptibility Testing of the National Committee for Clinical Laboratory Standards. Clin Infect Dis 24: 235–247.

136. SanglardD, KuchlerK, IscherF, PaganiJL, MonodM, et al. (1995) Mechanisms of resistance to azole antifungal agents in Candida albicans isolates from AIDS patients involve specific multidrug transporters. Antimicrob Agents Chemother 39: 2378–2386.