1932

Abstract

The last several decades have witnessed a surge in drug-resistant fungal infections that pose a serious threat to human health. While there is a limited arsenal of drugs that can be used to treat systemic infections, scientific advances have provided renewed optimism for the discovery of novel antifungals. The development of chemical-genomic assays using has provided powerful methods to identify the mechanism of action of molecules in a living cell. Advances in molecular biology techniques have enabled complementary assays to be developed in fungal pathogens, including and . These approaches enable the identification of target genes for drug candidates, as well as genes involved in buffering drug target pathways. Here, we examine yeast chemical-genomic assays and highlight how such resources can be utilized to predict the mechanisms of action of compounds, to study virulence attributes of diverse fungal pathogens, and to bolster the antifungal pipeline.

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2022-09-08
2024-12-06
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Literature Cited

  1. 1.
    Alby K, Bennett RJ. 2010. Sexual reproduction in the Candida clade: cryptic cycles, diverse mechanisms, and alternative functions. Cell Mol. Life Sci. 67:3275–85
    [Google Scholar]
  2. 2.
    Anderson TM, Clay MC, Cioffi AG, Diaz KA, Hisao GS et al. 2014. Amphotericin forms an extramembranous and fungicidal sterol sponge. Nat. Chem. Biol. 10:400–6
    [Google Scholar]
  3. 3.
    Arras SD, Chua SM, Wizrah MS, Faint JA, Yap AS, Fraser JA. 2016. Targeted genome editing via CRISPR in the pathogen Cryptococcus neoformans. PLOS ONE 11:e0164322
    [Google Scholar]
  4. 4.
    Bar-Yosef H, Gildor T, Ramirez-Zavala B, Schmauch C, Weissman Z et al. 2018. A global analysis of kinase function in Candida albicans hyphal morphogenesis reveals a role for the endocytosis regulator Akl1. Front. Cell Infect. Microbiol. 8:17
    [Google Scholar]
  5. 5.
    Becker JM, Kauffman SJ, Hauser M, Huang L, Lin M et al. 2010. Pathway analysis of Candida albicans survival and virulence determinants in a murine infection model. PNAS 107:22044–49
    [Google Scholar]
  6. 6.
    Bennett RJ, Johnson AD. 2005. Mating in Candida albicans and the search for a sexual cycle. Annu. Rev. Microbiol. 59:233–55
    [Google Scholar]
  7. 7.
    Blankenship JR, Mitchell AP. 2006. How to build a biofilm: a fungal perspective. Curr. Opin. Microbiol. 9:588–94
    [Google Scholar]
  8. 8.
    Borisy AA, Elliott PJ, Hurst NW, Lee MS, Lehar J et al. 2003. Systematic discovery of multicomponent therapeutics. PNAS 100:7977–82
    [Google Scholar]
  9. 9.
    Braun BR, van Het Hoog M, d'Enfert C, Martchenko M, Dungan J et al. 2005. A human-curated annotation of the Candida albicans genome. PLOS Genet 1:36–57
    [Google Scholar]
  10. 10.
    Brown ED, Wright GD. 2016. Antibacterial drug discovery in the resistance era. Nature 529:336–43
    [Google Scholar]
  11. 11.
    Brown GD, Denning DW, Gow NA, Levitz SM, Netea MG, White TC. 2012. Hidden killers: human fungal infections. Sci. Transl. Med. 4:165rv13
    [Google Scholar]
  12. 12.
    Brown GD, Denning DW, Levitz SM. 2012. Tackling human fungal infections. Science 336:647
    [Google Scholar]
  13. 13.
    Brown JC, Nelson J, VanderSluis B, Deshpande R, Butts A et al. 2014. Unraveling the biology of a fungal meningitis pathogen using chemical genetics. Cell 159:1168–87
    [Google Scholar]
  14. 14.
    Butts A, Koselny K, Chabrier-Rosello Y, Semighini CP, Brown JC et al. 2014. Estrogen receptor antagonists are anti-cryptococcal agents that directly bind EF hand proteins and synergize with fluconazole in vivo. mBio 5:e00765–13
    [Google Scholar]
  15. 15.
    Cabral V, Znaidi S, Walker LA, Martin-Yken H, Dague E et al. 2014. Targeted changes of the cell wall proteome influence Candida albicans ability to form single- and multi-strain biofilms. PLOS Pathog 10:e1004542
    [Google Scholar]
  16. 16.
    Caplan T, Lorente-Macias A, Stogios PJ, Evdokimova E, Hyde S et al. 2020. Overcoming fungal echinocandin resistance through inhibition of the non-essential stress kinase Yck2. Cell Chem. Biol. 27:269–82
    [Google Scholar]
  17. 17.
    Chauvel M, Nesseir A, Cabral V, Znaidi S, Goyard S et al. 2012. A versatile overexpression strategy in the pathogenic yeast Candida albicans: identification of regulators of morphogenesis and fitness. PLOS ONE 7:e45912
    [Google Scholar]
  18. 18.
    Chun CD, Brown JCS, Madhani HD. 2011. A major role for capsule-independent phagocytosis-inhibitory mechanisms in mammalian infection by Cryptococcus neoformans. Cell Host Microbe 9:243–51
    [Google Scholar]
  19. 19.
    Clatworthy AE, Pierson E, Hung DT 2007. Targeting virulence: a new paradigm for antimicrobial therapy. Nat. Chem. Biol. 3:541–48
    [Google Scholar]
  20. 20.
    Costanzo M, Baryshnikova A, Bellay J, Kim Y, Spear ED et al. 2010. The genetic landscape of a cell. Science 327:425–31
    [Google Scholar]
  21. 21.
    Costanzo M, Hou J, Messier V, Nelson J, Rahman M et al. 2021. Environmental robustness of the global yeast genetic interaction network. Science 372:eabf8424
    [Google Scholar]
  22. 22.
    Costanzo M, Kuzmin E, van Leeuwen J, Mair B, Moffat J et al. 2019. Global genetic networks and the genotype-to-phenotype relationship. Cell 177:85–100
    [Google Scholar]
  23. 23.
    Costanzo M, VanderSluis B, Koch EN, Baryshnikova A, Pons C et al. 2016. A global genetic interaction network maps a wiring diagram of cellular function. Science 353:aaf1420
    [Google Scholar]
  24. 24.
    Cowen LE, Lindquist S. 2005. Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi. Science 309:2185–89
    [Google Scholar]
  25. 25.
    Cowen LE, Singh SD, Kohler JR, Collins C, Zaas AK et al. 2009. Harnessing Hsp90 function as a powerful, broadly effective therapeutic strategy for fungal infectious disease. PNAS 106:2818–23
    [Google Scholar]
  26. 26.
    Cruz MC, Goldstein AL, Blankenship JR, Del Poeta M, Davis D et al. 2002. Calcineurin is essential for survival during membrane stress in Candida albicans. EMBO J 21:546–59
    [Google Scholar]
  27. 27.
    Dixon SJ, Costanzo M, Baryshnikova A, Andrews B, Boone C. 2009. Systematic mapping of genetic interaction networks. Annu. Rev. Genet. 43:601–25
    [Google Scholar]
  28. 28.
    Fan Y, Lin X. 2018. Multiple applications of a transient CRISPR-Cas9 coupled with electroporation (TRACE) system in the Cryptococcus neoformans species complex. Genetics 208:1357–72
    [Google Scholar]
  29. 29.
    Fisher MC, Gurr SJ, Cuomo CA, Blehert DS, Jin H et al. 2020. Threats posed by the fungal kingdom to humans, wildlife, and agriculture. mBio 11:e0044–20
    [Google Scholar]
  30. 30.
    Fu C, Zhang X, Veri AO, Iyer KR, Lash E et al. 2021. Leveraging machine learning essentiality predictions and chemogenomic interactions to identify antifungal targets. Nat. Commun. 12:16497
    [Google Scholar]
  31. 31.
    Gauwerky K, Borelli C, Korting HC. 2009. Targeting virulence: a new paradigm for antifungals. Drug Discov. Today 14:214–22
    [Google Scholar]
  32. 32.
    Ghaemmaghami S, Huh WK, Bower K, Howson RW, Belle A et al. 2003. Global analysis of protein expression in yeast. Nature 425:737–41
    [Google Scholar]
  33. 33.
    Giaever G, Chu AM, Ni L, Connelly C, Riles L et al. 2002. Functional profiling of the Saccharomyces cerevisiae genome. Nature 418:387–91
    [Google Scholar]
  34. 34.
    Giaever G, Flaherty P, Kumm J, Proctor M, Nislow C et al. 2004. Chemogenomic profiling: identifying the functional interactions of small molecules in yeast. PNAS 101:793–98
    [Google Scholar]
  35. 35.
    Giaever G, Shoemaker DD, Jones TW, Liang H, Winzeler EA et al. 1999. Genomic profiling of drug sensitivities via induced haploinsufficiency. Nat. Genet. 21:278–83
    [Google Scholar]
  36. 36.
    Goffeau A, Barrell BG, Bussey H, Davis RW, Dujon B et al. 1996. Life with 6000 genes. Science 274:54667
    [Google Scholar]
  37. 37.
    Goranov AI, Madhani HD. 2014. Functional profiling of human fungal pathogen genomes. Cold Spring Harb. . Perspect. Med. 5:a019596
    [Google Scholar]
  38. 38.
    Hai TP, Van AD, Ngan NTT, Nhat LTH, Lan NPH et al. 2019. The combination of tamoxifen with amphotericin B, but not with fluconazole, has synergistic activity against the majority of clinical isolates of Cryptococcus neoformans. Mycoses 62:818–25
    [Google Scholar]
  39. 39.
    Hartland CL, Youngsaye W, Morgan B, Ting A, Nag P et al. 2011. Identification of small molecules that selectively inhibit fluconazole-resistant Candida albicans in the presence of fluconazole but not in its absence–probe 2. Probe Reports from the NIH Molecular Libraries Program Bethesda, MD: National Cent. Biotechnol. Info https://pubmed.ncbi.nlm.nih.gov/22834037
    [Google Scholar]
  40. 40.
    Heitman J. 2005. Cell biology: a fungal Achilles' heel. Science 309:2175–76
    [Google Scholar]
  41. 41.
    Heitman J, Movva NR, Hall MN. 1991. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253:905–9
    [Google Scholar]
  42. 42.
    Hickman MA, Zeng G, Forche A, Hirakawa MP, Abbey D et al. 2013. The ‘obligate diploid’ Candida albicans forms mating-competent haploids. Nature 494:55–59
    [Google Scholar]
  43. 43.
    Hillenmeyer ME, Fung E, Wildenhain J, Pierce SE, Hoon S et al. 2008. The chemical genomic portrait of yeast: uncovering a phenotype for all genes. Science 320:362–65
    [Google Scholar]
  44. 44.
    Ho CH, Magtanong L, Barker SL, Gresham D, Nishimura S et al. 2009. A molecular barcoded yeast ORF library enables mode-of-action analysis of bioactive compounds. Nat. Biotechnol. 27:369–77
    [Google Scholar]
  45. 45.
    Homann OR, Dea J, Noble SM, Johnson AD. 2009. A phenotypic profile of the Candida albicans regulatory network. PLOS Genet 5:e1000783
    [Google Scholar]
  46. 46.
    Hoon S, Smith AM, Wallace IM, Suresh S, Miranda M et al. 2008. An integrated platform of genomic assays reveals small-molecule bioactivities. Nat. Chem. Biol. 4:498–506
    [Google Scholar]
  47. 47.
    Hoon S, St Onge RP, Giaever G, Nislow C. 2008. Yeast chemical genomics and drug discovery: an update. Trends Pharmacol. Sci. 29:499–504
    [Google Scholar]
  48. 48.
    Huang DS, LeBlanc EV, Shekhar-Guturja T, Robbins N, Krysan DJ et al. 2020. Design and synthesis of fungal-selective resorcylate aminopyrazole Hsp90 inhibitors. J. Med. Chem. 63:2139–80
    [Google Scholar]
  49. 49.
    Huang MY, Joshi MB, Boucher MJ, Lee S, Loza LC et al. 2022. Short homology-directed repair using optimized Cas9 in the pathogen Cryptococcus neoformans enables rapid gene deletion and tagging. Genetics 220:1iyab180
    [Google Scholar]
  50. 50.
    Huang Z, Chen K, Zhang J, Li Y, Wang H et al. 2013. A functional variomics tool for discovering drug-resistance genes and drug targets. Cell Rep 3:577–85
    [Google Scholar]
  51. 51.
    Iyer KR, Revie NM, Fu C, Robbins N, Cowen LE. 2021. Treatment strategies for cryptococcal infection: challenges, advances and future outlook. Nat. Rev. Microbiol. 19:454–66
    [Google Scholar]
  52. 52.
    Jiang B, Xu D, Allocco J, Parish C, Davison J et al. 2008. PAP inhibitor with in vivo efficacy identified by Candida albicans genetic profiling of natural products. Chem. Biol. 15:363–74
    [Google Scholar]
  53. 53.
    Jung KW, Yang DH, Maeng S, Lee KT, So YS et al. 2015. Systematic functional profiling of transcription factor networks in Cryptococcus neoformans. Nat. Commun. 6:6757
    [Google Scholar]
  54. 54.
    Juvvadi PR, Fox D 3rd, Bobay BG, Hoy MJ, Gobeil SMC et al. 2019. Harnessing calcineurin-FK506-FKBP12 crystal structures from invasive fungal pathogens to develop antifungal agents. Nat. Commun. 10:4275
    [Google Scholar]
  55. 55.
    Lamoth F, Juvvadi PR, Fortwendel JR, Steinbach WJ. 2012. Heat shock protein 90 is required for conidiation and cell wall integrity in Aspergillus fumigatus. Eukaryot. Cell 11:1324–32
    [Google Scholar]
  56. 56.
    LeBlanc EV, Polvi EJ, Veri AO, Prive GG, Cowen LE. 2020. Structure-guided approaches to targeting stress responses in human fungal pathogens. J. Biol. Chem. 295:14458–72
    [Google Scholar]
  57. 57.
    Lee AY, St Onge RP, Proctor MJ, Wallace IM, Nile AH et al. 2014. Mapping the cellular response to small molecules using chemogenomic fitness signatures. Science 344:208–11
    [Google Scholar]
  58. 58.
    Lee JA, Robbins N, Xie JL, Ketela T, Cowen LE. 2016. Functional genomic analysis of Candida albicans adherence reveals a key role for the Arp2/3 complex in cell wall remodelling and biofilm formation. PLOS Genet 12:e1006452
    [Google Scholar]
  59. 59.
    Lee KT, Hong J, Lee DG, Lee M, Cha S et al. 2020. Fungal kinases and transcription factors regulating brain infection in Cryptococcus neoformans. Nat. Commun. 11:1521
    [Google Scholar]
  60. 60.
    Lee KT, So YS, Yang DH, Jung KW, Choi J et al. 2016. Systematic functional analysis of kinases in the fungal pathogen Cryptococcus neoformans. Nat. Commun. 7:12766
    [Google Scholar]
  61. 61.
    Lee Y, Puumala E, Robbins N, Cowen LE. 2020. Antifungal drug resistance: molecular mechanisms in Candida albicans and beyond. Chem. Rev. 121:3390–411
    [Google Scholar]
  62. 62.
    Lipinski CA. 2004. Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov. Today Technol. 1:337–41
    [Google Scholar]
  63. 63.
    Liston SD, Whitesell L, Kapoor M, Shaw KJ, Cowen LE. 2020. Enhanced efflux pump expression in Candida mutants results in decreased manogepix susceptibility. Antimicrob. Agents Chemother. 64:e00261–20
    [Google Scholar]
  64. 64.
    Liu OW, Chun CD, Chow ED, Chen C, Madhani HD, Noble SM. 2008. Systematic genetic analysis of virulence in the human fungal pathogen Cryptococcus neoformans. Cell 135:174–88
    [Google Scholar]
  65. 65.
    Lum PY, Armour CD, Stepaniants SB, Cavet G, Wolf MK et al. 2004. Discovering modes of action for therapeutic compounds using a genome-wide screen of yeast heterozygotes. Cell 116:121–37
    [Google Scholar]
  66. 66.
    Mann PA, McLellan CA, Koseoglu S, Si Q, Kuzmin E et al. 2015. Chemical genomics-based antifungal drug discovery: targeting glycosylphosphatidylinositol (GPI) precursor biosynthesis. ACS Infect. Dis. 1:59–72
    [Google Scholar]
  67. 67.
    Martzen MR, McCraith SM, Spinelli SL, Torres FM, Fields S et al. 1999. A biochemical genomics approach for identifying genes by the activity of their products. Science 286:1153–55
    [Google Scholar]
  68. 68.
    Mor V, Rella A, Farnoud AM, Singh A, Munshi M et al. 2015. Identification of a new class of antifungals targeting the synthesis of fungal sphingolipids. mBio 6:e00647
    [Google Scholar]
  69. 69.
    Mutz M, Roemer T. 2016. The GPI anchor pathway: a promising antifungal target?. Future Med. Chem. 8:1387–91
    [Google Scholar]
  70. 70.
    Nargesi S, Bongomin F, Hedayati MT. 2021. The impact of COVID-19 pandemic on AIDS-related mycoses and fungal neglected tropical diseases: Why should we worry?. PLOS Negl. Trop. Dis. 15:e0009092
    [Google Scholar]
  71. 71.
    Nelson J, Simpkins SW, Safizadeh H, Li SC, Piotrowski JS et al. 2018. MOSAIC: a chemical-genetic interaction data repository and web resource for exploring chemical modes of action. Bioinformatics 34:1251–52
    [Google Scholar]
  72. 72.
    Nijman SM. 2015. Functional genomics to uncover drug mechanism of action. Nat. Chem. Biol. 11:942–48
    [Google Scholar]
  73. 73.
    Noble SM, French S, Kohn LA, Chen V, Johnson AD 2010. Systematic screens of a Candida albicans homozygous deletion library decouple morphogenetic switching and pathogenicity. Nat. Genet. 42:590–98
    [Google Scholar]
  74. 74.
    Noble SM, Gianetti BA, Witchley JN. 2017. Candida albicans cell-type switching and functional plasticity in the mammalian host. Nat. Rev. Microbiol. 15:96–108
    [Google Scholar]
  75. 75.
    O'Meara TR, Robbins N, Cowen LE. 2017. The Hsp90 chaperone network modulates Candida virulence traits. Trends Microbiol 25:809–19
    [Google Scholar]
  76. 76.
    O'Meara TR, Veri A, Ketela T, Jiang B, Roemer T, Cowen LE. 2015. Global analysis of fungal morphology exposes mechanisms of host cell escape. Nat. Commun. 6:6741
    [Google Scholar]
  77. 77.
    Parsons AB, Lopez A, Givoni IE, Williams DE, Gray CA et al. 2006. Exploring the mode-of-action of bioactive compounds by chemical-genetic profiling in yeast. Cell 126:611–25
    [Google Scholar]
  78. 78.
    Perfect JR. 2017. The antifungal pipeline: a reality check. Nat. Rev. Drug Discov. 16:603–16
    [Google Scholar]
  79. 79.
    Pfaller MA, Huband MD, Flamm RK, Bien PA, Castanheira M. 2019. In vitro activity of APX001A (Manogepix) and comparator agents against 1,706 fungal isolates collected during an international surveillance program in 2017. Antimicrob. Agents Chemother. 63:e00840–19
    [Google Scholar]
  80. 80.
    Piotrowski JS, Li SC, Deshpande R, Simpkins SW, Nelson J et al. 2017. Functional annotation of chemical libraries across diverse biological processes. Nat. Chem. Biol. 13:982–93
    [Google Scholar]
  81. 81.
    Pouliot M, Jeanmart S. 2016. Pan assay interference compounds (PAINS) and other promiscuous compounds in antifungal research. J. Med. Chem. 59:497–503
    [Google Scholar]
  82. 82.
    Prelich G. 2012. Gene overexpression: uses, mechanisms, and interpretation. Genetics 190:841–54
    [Google Scholar]
  83. 83.
    Raut A, Huy NT. 2021. Rising incidence of mucormycosis in patients with COVID-19: another challenge for India amidst the second wave?. Lancet Respir. Med. 9:e77
    [Google Scholar]
  84. 84.
    Revie NM, Iyer KR, Robbins N, Cowen LE. 2018. Antifungal drug resistance: evolution, mechanisms and impact. Curr. Opin. Microbiol. 45:70–76
    [Google Scholar]
  85. 85.
    Rhein J, Morawski BM, Hullsiek KH, Nabeta HW, Kiggundu R et al. 2016. Efficacy of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis: an open-label dose-ranging study. Lancet Infect. Dis. 16:809–18
    [Google Scholar]
  86. 86.
    Robbins N, Caplan T, Cowen LE. 2017. Molecular evolution of antifungal drug resistance. Annu. Rev. Microbiol. 71:753–75
    [Google Scholar]
  87. 87.
    Robbins N, Spitzer M, Yu T, Cerone RP, Averette AK et al. 2015. An antifungal combination matrix identifies a rich pool of adjuvant molecules that enhance drug activity against diverse fungal pathogens. Cell Rep 13:1481–92
    [Google Scholar]
  88. 88.
    Robbins N, Uppuluri P, Nett J, Rajendran R, Ramage G et al. 2011. Hsp90 governs dispersion and drug resistance of fungal biofilms. PLOS Pathog 7:e1002257
    [Google Scholar]
  89. 89.
    Robbins N, Wright GD, Cowen LE. 2016. Antifungal drugs: the current armamentarium and development of new agents. Microbiol. Spectr. 4:FUNK–00022016
    [Google Scholar]
  90. 90.
    Rodriguez-Suarez R, Xu D, Veillette K, Davison J, Sillaots S et al. 2007. Mechanism-of-action determination of GMP synthase inhibitors and target validation in Candida albicans and Aspergillus fumigatus. . Chem. Biol. 14:1163–75
    [Google Scholar]
  91. 91.
    Roemer T, Boone C. 2013. Systems-level antimicrobial drug and drug synergy discovery. Nat. Chem. Biol. 9:222–31
    [Google Scholar]
  92. 92.
    Roemer T, Davies J, Giaever G, Nislow C. 2012. Bugs, drugs and chemical genomics. Nat. Chem. Biol. 8:46–56
    [Google Scholar]
  93. 93.
    Roemer T, Jiang B, Davison J, Ketela T, Veillette K et al. 2003. Large-scale essential gene identification in Candida albicans and applications to antifungal drug discovery. Mol. Microbiol. 50:167–81
    [Google Scholar]
  94. 94.
    Roemer T, Krysan DJ. 2014. Antifungal drug development: challenges, unmet clinical needs, and new approaches. Cold Spring Harb. . Perspect. Med. 4:a019703
    [Google Scholar]
  95. 95.
    Roemer T, Xu D, Singh SB, Parish CA, Harris G et al. 2011. Confronting the challenges of natural product-based antifungal discovery. Chem. Biol. 18:148–64
    [Google Scholar]
  96. 96.
    Sahni N, Yi S, Daniels KJ, Huang G, Srikantha T, Soll DR. 2010. Tec1 mediates the pheromone response of the white phenotype of Candida albicans: insights into the evolution of new signal transduction pathways. PLOS Biol 8:e1000363
    [Google Scholar]
  97. 97.
    Segal ES, Gritsenko V, Levitan A, Yadav B, Dror N et al. 2018. Gene essentiality analyzed by in vivo transposon mutagenesis and machine learning in a stable haploid isolate of Candida albicans. mBio 9:e02048–18
    [Google Scholar]
  98. 98.
    Shekhar-Guturja T, Gunaherath GM, Wijeratne EM, Lambert JP, Averette AF et al. 2016. Dual action antifungal small molecule modulates multidrug efflux and TOR signaling. Nat. Chem. Biol. 12:867–75
    [Google Scholar]
  99. 99.
    Shoemaker DD, Lashkari DA, Morris D, Mittmann M, Davis RW. 1996. Quantitative phenotypic analysis of yeast deletion mutants using a highly parallel molecular bar-coding strategy. Nat. Genet. 14:450–56
    [Google Scholar]
  100. 100.
    Simpkins SW, Deshpande R, Nelson J, Li SC, Piotrowski JS et al. 2019. Using BEAN-counter to quantify genetic interactions from multiplexed barcode sequencing experiments. Nat. Protoc. 14:415–40
    [Google Scholar]
  101. 101.
    Smith AM, Ammar R, Nislow C, Giaever G. 2010. A survey of yeast genomic assays for drug and target discovery. Pharmacol. Ther. 127:156–64
    [Google Scholar]
  102. 102.
    Sopko R, Huang D, Preston N, Chua G, Papp B et al. 2006. Mapping pathways and phenotypes by systematic gene overexpression. Mol. Cell 21:319–30
    [Google Scholar]
  103. 103.
    Spitzer M, Griffiths E, Blakely KM, Wildenhain J, Ejim L et al. 2011. Cross-species discovery of syncretic drug combinations that potentiate the antifungal fluconazole. Mol. Syst. Biol. 7:499
    [Google Scholar]
  104. 104.
    Steinbach WJ, Cramer RA Jr., Perfect BZ, Asfaw YG, Sauer TC et al. 2006. Calcineurin controls growth, morphology, and pathogenicity in Aspergillus fumigatus. . Eukaryot. Cell 5:1091–103
    [Google Scholar]
  105. 105.
    Thevissen K, de Mello Tavares P, Xu D, Blankenship J, Vandenbosch D et al. 2012. The plant defensin RsAFP2 induces cell wall stress, septin mislocalization and accumulation of ceramides in Candida albicans. Mol. Microbiol. 84:166–80
    [Google Scholar]
  106. 106.
    Tong AH, Evangelista M, Parsons AB, Xu H, Bader GD et al. 2001. Systematic genetic analysis with ordered arrays of yeast deletion mutants. Science 294:2364–68
    [Google Scholar]
  107. 107.
    Tong AH, Lesage G, Bader GD, Ding H, Xu H et al. 2004. Global mapping of the yeast genetic interaction network. Science 303:808–13
    [Google Scholar]
  108. 108.
    Wambaugh MA, Denham ST, Ayala M, Brammer B, Stonhill MA, Brown JC. 2020. Synergistic and antagonistic drug interactions in the treatment of systemic fungal infections. eLife 9:e54160
    [Google Scholar]
  109. 109.
    Wang P. 2018. Two distinct approaches for CRISPR-Cas9-mediated gene editing in Cryptococcus neoformans and related species. mSphere 3:e00208–18
    [Google Scholar]
  110. 110.
    Wang Y, Wei D, Zhu X, Pan J, Zhang P et al. 2016. A ‘suicide’ CRISPR-Cas9 system to promote gene deletion and restoration by electroporation in Cryptococcus neoformans. Sci. Rep. 6:31145
    [Google Scholar]
  111. 111.
    Wassermann AM, Lounkine E, Hoepfner D, Le Goff G, King FJ et al. 2015. Dark chemical matter as a promising starting point for drug lead discovery. Nat. Chem. Biol. 11:958–66
    [Google Scholar]
  112. 112.
    Whitesell L, Robbins N, Huang DS, McLellan CA, Shekhar-Guturja T et al. 2019. Structural basis for species-selective targeting of Hsp90 in a pathogenic fungus. Nat. Commun. 10:402
    [Google Scholar]
  113. 113.
    Winzeler EA, Shoemaker DD, Astromoff A, Liang H, Anderson K et al. 1999. Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis. Science 285:901–6
    [Google Scholar]
  114. 114.
    Witchley JN, Penumetcha P, Abon NV, Woolford CA, Mitchell AP, Noble SM. 2019. Candida albicans morphogenesis programs control the balance between gut commensalism and invasive infection. Cell Host Microbe 25:432–43.e6
    [Google Scholar]
  115. 115.
    Xu D, Jiang B, Ketela T, Lemieux S, Veillette K et al. 2007. Genome-wide fitness test and mechanism-of-action studies of inhibitory compounds in Candida albicans. PLOS Pathog 3:e92
    [Google Scholar]
  116. 116.
    Xu D, Sillaots S, Davison J, Hu W, Jiang B et al. 2009. Chemical genetic profiling and characterization of small-molecule compounds that affect the biosynthesis of unsaturated fatty acids in Candida albicans. J. Biol. Chem. 284:19754–64
    [Google Scholar]
  117. 117.
    Xue A, Robbins N, Cowen LE. 2020. Advances in fungal chemical genomics for the discovery of new antifungal agents. Ann. N. Y. Acad. Sci. 1496:5–22
    [Google Scholar]
  118. 118.
    Yan Z, Costanzo M, Heisler LE, Paw J, Kaper F et al. 2008. Yeast Barcoders: a chemogenomic application of a universal donor-strain collection carrying bar-code identifiers. Nat. Methods 5:719–25
    [Google Scholar]
  119. 119.
    Zhang F, Zhao M, Braun DR, Ericksen SS, Piotrowski JS et al. 2020. A marine microbiome antifungal targets urgent-threat drug-resistant fungi. Science 370:974–78
    [Google Scholar]
  120. 120.
    Znaidi S, van Wijlick L, Hernandez-Cervantes A, Sertour N, Desseyn JL et al. 2018. Systematic gene overexpression in Candida albicans identifies a regulator of early adaptation to the mammalian gut. Cell Microbiol 20:e12890
    [Google Scholar]
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/content/journals/10.1146/annurev-micro-041020-094524
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  • Article Type: Review Article
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