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Using Yeast to Discover Inhibitors of Multidrug Efflux in Candida albicans

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Candida albicans: Cellular and Molecular Biology

Abstract

Fungal infections range from mild readily treated conditions such athlete’s foot or thrush to life-threatening illnesses that affect immunocompromised or immunosuppressed patients. The antimycotic azole drugs, which target the enzyme lanosterol 14α-demethylase required for ergosterol biosynthesis, have provided therapy for a wide range of fungal infections over several decades. However, significant resistance is conferred by the removal of azole drugs from fungal cells via multidrug efflux pumps belong to the ABCG class of ATP-binding cassette transporters and a DHA1 class major facilitator superfamily efflux pump. This chapter will describe how the genetically tractable and biochemically well-characterised yeast Saccharomyces cerevisiae has provided a platform for the discovery and testing of novel inhibitors of these two classes of drug efflux pump in fungal pathogens of humans.

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References

  • Akins RA (2005) An update on antifungal targets and mechanisms of resistance in Candida albicans. Med Mycol 43(4):285–318

    Article  CAS  PubMed  Google Scholar 

  • Alarco AM, Raymond M (1999) The bZip transcription factor Cap1p is involved in multidrug resistance and oxidative stress response in Candida albicans. J Bacteriol 181(3):700–708

    CAS  PubMed  PubMed Central  Google Scholar 

  • Aller SG, Yu J, Ward A, Weng Y, Chittaboina S, Zhuo R, Harrell PM, Trinh YT, Zhang Q, Urbatsch IL, Chang G (2009) Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science 323(5922):1718–1722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Asmundsdottir LR, Erlendsdottir H, Haraldsson G, Guo H, Xu J, Gottfredsson M (2008) Molecular epidemiology of candidemia: evidence of clusters of smoldering nosocomial infections. Clin Infect Dis 47(2):e17–24. doi:10.1086/589298

    Article  PubMed  Google Scholar 

  • Azevedo MM, Faria-Ramos I, Cruz LC, Pina-Vaz C, Rodrigues AG (2015) Genesis of azole antifungal resistance from agriculture to clinical settings. J Agric Food Chem 63(34):7463–7468. doi:10.1021/acs.jafc.5b02728

    Article  CAS  PubMed  Google Scholar 

  • Babu M, Vlasblom J, Pu S, Guo X, Graham C, Bean BD, Burston HE, Vizeacoumar FJ, Snider J, Phanse S, Fong V, Tam YY, Davey M, Hnatshak O, Bajaj N, Chandran S, Punna T, Christopolous C, Wong V, Yu A, Zhong G, Li J, Stagljar I, Conibear E, Wodak SJ, Emili A, Greenblatt JF (2012) Interaction landscape of membrane-protein complexes in Saccharomyces cerevisiae. Nature 489(7417):585–589. doi:10.1038/nature11354

    Article  CAS  PubMed  Google Scholar 

  • Baetz K, McHardy L, Gable K, Tarling T, Reberioux D, Bryan J, Andersen RJ, Dunn T, Hieter P, Roberge M (2004) Yeast genome-wide drug-induced haploinsufficiency screen to determine drug mode of action. Proc Natl Acad Sci USA 101(13):4525–4530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Balzi E, Goffeau A (1995) Yeast multidrug resistance: the PDR network. J Bioenerg Biomembr 27(1):71–76

    Article  CAS  PubMed  Google Scholar 

  • Bauer BE, Wolfger H, Kuchler K (1999) Inventory and function of yeast ABC proteins: about sex, stress, pleiotropic drug and heavy metal resistance. Biochim Biophys Acta 1461(2):217–236

    Article  CAS  PubMed  Google Scholar 

  • Becher R, Wirsel SG (2012) Fungal cytochrome P450 sterol 14alpha-demethylase (CYP51) and azole resistance in plant and human pathogens. Appl Microbiol Biotechnol 95(4):825–840. doi:10.1007/s00253-012-4195-9

    Article  CAS  PubMed  Google Scholar 

  • Bennett JE, Izumikawa K, Marr KA (2004) Mechanism of increased fluconazole resistance in Candida glabrata during prophylaxis. Antimicrob Agents Chemother 48(5):1773–1777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Berman J (2016) Ploidy plasticity: a rapid and reversible strategy for adaptation to stress. FEMS Yeast Res 16(3). doi:10.1093/femsyr/fow020

  • Billack B, Santoro M, Lau-Cam C (2009) Growth inhibitory action of ebselen on fluconazole-resistant Candida albicans: role of the plasma membrane H+-ATPase. Microb Drug Resist 15(2):77–83. doi:10.1089/mdr.2009.0872

    Article  CAS  PubMed  Google Scholar 

  • Blackwell M (2011) The fungi: 1, 2, 3 … 5.1 million species? Am J Bot 98(3):426–438. doi:10.3732/ajb.1000298

    Article  PubMed  Google Scholar 

  • Bouige P, Laurent D, Piloyan L, Dassa E (2002) Phylogenetic and functional classification of ATP-binding cassette (ABC) systems. Curr Protein Pept Sci 3(5):541–559

    Article  CAS  PubMed  Google Scholar 

  • Campbell BC, Chan KL, Kim JH (2012) Chemosensitization as a means to augment commercial antifungal agents. Front Microbiol 3:79. doi:10.3389/fmicb.2012.00079

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cannon RD, Lamping E, Holmes AR, Niimi K, Baret PV, Keniya MV, Tanabe K, Niimi M, Goffeau A, Monk BC (2009) Efflux-mediated antifungal drug resistance. Clin Microbiol Rev 22(2):291–321. doi:10.1128/CMR.00051-08

  • Castrillo JI, Zeef LA, Hoyle DC, Zhang N, Hayes A, Gardner DC, Cornell MJ, Petty J, Hakes L, Wardleworth L, Rash B, Brown M, Dunn WB, Broadhurst D, O’Donoghue K, Hester SS, Dunkley TP, Hart SR, Swainston N, Li P, Gaskell SJ, Paton NW, Lilley KS, Kell DB, Oliver SG (2007) Growth control of the eukaryote cell: a systems biology study in yeast. J Biol 6(2):4

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen J, Li H, Li R, Bu D, Wan Z (2005) Mutations in the cyp51A gene and susceptibility to itraconazole in Aspergillus fumigatus serially isolated from a patient with lung aspergilloma. J Antimicrob Chemother 55(1):31–37

    Article  CAS  PubMed  Google Scholar 

  • Chen SH, Sheng CQ, Xu XH, Jiang YY, Zhang WN, He C (2007) Identification of Y118 amino acid residue in Candida albicans sterol 14alpha-demethylase associated with the enzyme activity and selective antifungal activity of azole analogues. Biol Pharm Bull 30(7):1246–1253

    Article  CAS  PubMed  Google Scholar 

  • Chen G, Bradford WD, Seidel CW, Li R (2012) Hsp90 stress potentiates rapid cellular adaptation through induction of aneuploidy. Nature 482(7384):246–250. doi:10.1038/nature10795

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chowdhary A, Kathuria S, Xu J, Meis JF (2013) Emergence of azole-resistant Aspergillus fumigatus strains due to agricultural azole use creates an increasing threat to human health. PLoS Pathog 9(10):e1003633. doi:10.1371/journal.ppat.1003633

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Claverys JP, Martin B, Havarstein LS (2007) Competence-induced fratricide in streptococci. Mol Microbiol 64(6):1423–1433. doi:10.1111/j.1365-2958.2007.05757.x

    Article  CAS  PubMed  Google Scholar 

  • Costa C, Dias PJ, Sa-Correia I, Teixeira MC (2014) MFS multidrug transporters in pathogenic fungi: do they have real clinical impact? Front Physiol 5:197. doi:10.3389/fphys.2014.00197

    PubMed  PubMed Central  Google Scholar 

  • Coste AT, Karababa M, Ischer F, Bille J, Sanglard D (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(6):1639–1652. doi:10.1128/EC.3.6.1639-1652.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Coste A, Turner V, Ischer F, Morschhauser J, Forche A, Selmecki A, Berman J, Bille J, Sanglard D (2006) A mutation in Tac1p, a transcription factor regulating CDR1 and CDR2, is coupled with loss of heterozygosity at chromosome 5 to mediate antifungal resistance in Candida albicans. Genetics 172(4):2139–2156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Coste A, Selmecki A, Forche A, Diogo D, Bougnoux ME, d’Enfert C, Berman J, Sanglard D (2007) Genotypic evolution of azole resistance mechanisms in sequential Candida albicans isolates. Eukaryot Cell 6(10):1889–1904. doi:10.1128/EC.00151-07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Coste AT, Crittin J, Bauser C, Rohde B, Sanglard D (2009) Functional analysis of cis- and trans-acting elements of the Candida albicans CDR2 promoter with a novel promoter reporter system. Eukaryot Cell 8(8):1250–1267. doi:10.1128/EC.00069-09

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cowen LE, Lindquist S (2005) Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi. Science 309(5744):2185–2189

    Article  CAS  PubMed  Google Scholar 

  • Cowen LE, Anderson JB, Kohn LM (2002) Evolution of drug resistance in Candida albicans. Annu Rev Microbiol 56:139–165. doi:10.1146/annurev.micro.56.012302.160907

    Article  CAS  PubMed  Google Scholar 

  • Cowen LE, Carpenter AE, Matangkasombut O, Fink GR, Lindquist S (2006) Genetic architecture of Hsp90-dependent drug resistance. Eukaryot Cell 5(12):2184–2188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cross EW, Park S, Perlin DS (2000) Cross-Resistance of clinical isolates of Candida albicans and Candida glabrata to over-the-counter azoles used in the treatment of vaginitis. Microb Drug Resist 6(2):155–161. doi:10.1089/107662900419474

    Article  CAS  PubMed  Google Scholar 

  • Crouzet J, Trombik T, Fraysse AS, Boutry M (2006) Organization and function of the plant pleiotropic drug resistance ABC transporter family. FEBS Lett 580(4):1123–1130

    Article  CAS  PubMed  Google Scholar 

  • Cruz MC, Goldstein AL, Blankenship JR, Del Poeta M, Davis D, Cardenas ME, Perfect JR, McCusker JH, Heitman J (2002) Calcineurin is essential for survival during membrane stress in Candida albicans. EMBO J 21(4):546–559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • da Silva Ferreira ME, Capellaro JL, dos Reis ME, Malavazi I, Perlin D, Park S, Anderson JB, Colombo AL, Arthington-Skaggs BA, Goldman MH, Goldman GH (2004) In vitro evolution of itraconazole resistance in Aspergillus fumigatus involves multiple mechanisms of resistance. Antimicrob Agents Chemother 48(11):4405–4413

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dassa E, Bouige P (2001) The ABC of ABCS: a phylogenetic and functional classification of ABC systems in living organisms. Res Microbiol 152(3–4):211–229

    Article  CAS  PubMed  Google Scholar 

  • Dawson RJ, Locher KP (2006) Structure of a bacterial multidrug ABC transporter. Nature 443(7108):180–185

    Article  CAS  PubMed  Google Scholar 

  • Dean M (2002) The human ATP-binding cassette (ABC) transporter superfamily. NCBI; available online at the NCBI Bookshelf: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mono_001&part=A137

  • Decottignies A, Goffeau A (1997) Complete inventory of the yeast ABC proteins. Nat Genet 15(2):137–145. doi:10.1038/ng0297-137

    Article  CAS  PubMed  Google Scholar 

  • Decottignies A, Kolaczkowski M, Balzi E, Goffeau A (1994) Solubilization and characterization of the overexpressed PDR5 multidrug resistance nucleotide triphosphatase of yeast. J Biol Chem 269(17):12797–12803

    CAS  PubMed  Google Scholar 

  • Decottignies A, Lambert L, Catty P, Degand H, Epping EA, Moye-Rowley WS, Balzi E, Goffeau A (1995) Identification and characterization of SNQ2, a new multidrug ATP binding cassette transporter of the yeast plasma membrane. J Biol Chem 270(30):18150–18157

    Article  CAS  PubMed  Google Scholar 

  • Decottignies A, Grant AM, Nichols JW, de Wet H, McIntosh DB, Goffeau A (1998) ATPase and multidrug transport activities of the overexpressed yeast ABC protein Yor1p. J Biol Chem 273(20):12612–12622

    Article  CAS  PubMed  Google Scholar 

  • Deng D, Xu C, Sun P, Wu J, Yan C, Hu M, Yan N (2014) Crystal structure of the human glucose transporter GLUT1. Nature 510(7503):121–125. doi:10.1038/nature13306

    Article  CAS  PubMed  Google Scholar 

  • Denning DW, Bromley MJ (2015) Infectious disease. How to bolster the antifungal pipeline. Science 347(6229):1414–1416. doi:10.1126/science.aaa6097

  • DeRisi J, van den Hazel B, Marc P, Balzi E, Brown P, Jacq C, Goffeau A (2000) Genome microarray analysis of transcriptional activation in multidrug resistance yeast mutants. FEBS Lett 470(2):156–160

    Article  CAS  PubMed  Google Scholar 

  • Deutschbauer AM, Jaramillo DF, Proctor M, Kumm J, Hillenmeyer ME, Davis RW, Nislow C, Giaever G (2005) Mechanisms of haploinsufficiency revealed by genome-wide profiling in yeast. Genetics 169(4):1915–1925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Digirolamo JA, Li XC, Jacob MR, Clark AM, Ferreira D (2009) Reversal of fluconazole resistance by sulfated sterols from the marine sponge Topsentia sp. J Nat Prod 72(8):1524–1528. doi:10.1021/np900177m

  • Diwischek F, Morschhauser J, Holzgrabe U (2009) Cerulenin analogues as inhibitors of efflux pumps in drug-resistant Candida albicans. Arch Pharm (Weinheim) 342(3):150–164. doi:10.1002/ardp.200800160

    Article  CAS  Google Scholar 

  • Dornetshuber R, Heffeter P, Sulyok M, Schumacher R, Chiba P, Kopp S, Koellensperger G, Micksche M, Lemmens-Gruber R, Berger W (2009) Interactions between ABC-transport proteins and the secondary Fusarium metabolites enniatin and beauvericin. Mol Nutr Food Res 53(7):904–920. doi:10.1002/mnfr.200800384

    Article  CAS  PubMed  Google Scholar 

  • Dujon B, Sherman D, Fischer G, Durrens P, Casaregola S, Lafontaine I, De Montigny J, Marck C, Neuveglise C, Talla E, Goffard N, Frangeul L, Aigle M, Anthouard V, Babour A, Barbe V, Barnay S, Blanchin S, Beckerich JM, Beyne E, Bleykasten C, Boisrame A, Boyer J, Cattolico L, Confanioleri F, De Daruvar A, Despons L, Fabre E, Fairhead C, Ferry-Dumazet H, Groppi A, Hantraye F, Hennequin C, Jauniaux N, Joyet P, Kachouri R, Kerrest A, Koszul R, Lemaire M, Lesur I, Ma L, Muller H, Nicaud JM, Nikolski M, Oztas S, Ozier-Kalogeropoulos O, Pellenz S, Potier S, Richard GF, Straub ML, Suleau A, Swennen D, Tekaia F, Wesolowski-Louvel M, Westhof E, Wirth B, Zeniou-Meyer M, Zivanovic I, Bolotin-Fukuhara M, Thierry A, Bouchier C, Caudron B, Scarpelli C, Gaillardin C, Weissenbach J, Wincker P, Souciet JL (2004) Genome evolution in yeasts. Nature 430(6995):35–44

    Article  PubMed  Google Scholar 

  • Dunkel N, Blass J, Rogers PD, Morschhauser J (2008a) 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(4):827–840. doi:10.1111/j.1365-2958.2008.06309.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dunkel N, Liu TT, Barker KS, Homayouni R, Morschhauser J, Rogers PD (2008b) 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(7):1180–1190. doi:10.1128/EC.00103-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eckford PD, Sharom FJ (2009) ABC efflux pump-based resistance to chemotherapy drugs. Chem Rev 109(7):2989–3011. doi:10.1021/cr9000226

    Article  CAS  PubMed  Google Scholar 

  • Edlind TD, Katiyar SK (2004) The echinocandin “target” identified by cross-linking is a homolog of Pil1 and Lsp1, sphingolipid-dependent regulators of cell wall integrity signaling. Antimicrob Agents Chemother 48(11):4491

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ernst R, Kueppers P, Klein CM, Schwarzmueller T, Kuchler K, Schmitt L (2008) A mutation of the H-loop selectively affects rhodamine transport by the yeast multidrug ABC transporter Pdr5. Proc Natl Acad Sci USA 105(13):5069–5074

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Esquivel BD, Smith AR, Zavrel M, White TC (2015) Azole drug import into the pathogenic fungus Aspergillus fumigatus. Antimicrob Agents Chemother 59(6):3390–3398. doi:10.1128/AAC.05003-14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fardeau V, Lelandais G, Oldfield A, Salin H, Lemoine S, Garcia M, Tanty V, Le Crom S, Jacq C, Devaux F (2007) The central role of PDR1 in the foundation of yeast drug resistance. J Biol Chem 282(7):5063–5074. doi:10.1074/jbc.M610197200

    Article  CAS  PubMed  Google Scholar 

  • Favre B, Ryder NS (1997) Cloning and expression of squalene epoxidase from the pathogenic yeast Aspergillus fumigatus. Gene 189(1):119–126

    Article  CAS  PubMed  Google Scholar 

  • Ferreira ME, Colombo AL, Paulsen I, Ren Q, Wortman J, Huang J, Goldman MH, Goldman GH (2005) The ergosterol biosynthesis pathway, transporter genes, and azole resistance in Aspergillus fumigatus. Med Mycol 43(Suppl 1):S313–319

    Article  PubMed  CAS  Google Scholar 

  • Ferreira-Pereira A, Marco S, Decottignies A, Nader J, Goffeau A, Rigaud JL (2003) Three-dimensional reconstruction of the Saccharomyces cerevisiae multidrug resistance protein Pdr5p. J Biol Chem 278(14):11995–11999. doi:10.1074/jbc.M212198200

    Article  CAS  PubMed  Google Scholar 

  • Fischer G, Rocha EP, Brunet F, Vergassola M, Dujon B (2006) Highly variable rates of genome rearrangements between hemiascomycetous yeast lineages. PLoS Genet 2(3):e32

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fitzpatrick DA, Logue ME, Stajich JE, Butler G (2006) A fungal phylogeny based on 42 complete genomes derived from supertree and combined gene analysis. BMC Evol Biol 6:99

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fleming JA, Lightcap ES, Sadis S, Thoroddsen V, Bulawa CE, Blackman RK (2002) Complementary whole-genome technologies reveal the cellular response to proteasome inhibition by PS-341. Proc Natl Acad Sci USA 99(3):1461–1466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fluman N, Bibi E (2009) Bacterial multidrug transport through the lens of the major facilitator superfamily. Biochim Biophys Acta 1794(5):738–747. doi:10.1016/j.bbapap.2008.11.020

    Article  CAS  PubMed  Google Scholar 

  • Ford CB, Funt JM, Abbey D, Issi L, Guiducci C, Martinez DA, Delorey T, Li BY, White TC, Cuomo C, Rao RP, Berman J, Thompson DA, Regev A (2015) The evolution of drug resistance in clinical isolates of Candida albicans Elife 4:e00662. doi:10.7554/eLife.00662

    PubMed  Google Scholar 

  • Galagan JE, Calvo SE, Cuomo C, Ma LJ, Wortman JR, Batzoglou S, Lee SI, Basturkmen M, Spevak CC, Clutterbuck J, Kapitonov V, Jurka J, Scazzocchio C, Farman M, Butler J, Purcell S, Harris S, Braus GH, Draht O, Busch S, D’Enfert C, Bouchier C, Goldman GH, Bell-Pedersen D, Griffiths-Jones S, Doonan JH, Yu J, Vienken K, Pain A, Freitag M, Selker EU, Archer DB, Penalva MA, Oakley BR, Momany M, Tanaka T, Kumagai T, Asai K, Machida M, Nierman WC, Denning DW, Caddick M, Hynes M, Paoletti M, Fischer R, Miller B, Dyer P, Sachs MS, Osmani SA, Birren BW (2005) Sequencing of Aspergillus nidulans and comparative analysis with A. fumigates and A. oryzae. Nature 438(7071):1105–1115

    Google Scholar 

  • Galagan JE, Henn MR, Ma L-J, Cuomo CA, Biren B (2007) Genomics of the fungal kingdom: insights into eukaryotic biology. Genome Res 15:1620–1631

    Article  CAS  Google Scholar 

  • Gaur M, Choudhury D, Prasad R (2005) Complete inventory of ABC proteins in human pathogenic yeast, Candida albicans. J Mol Microbiol Biotechnol 9(1):3–15

    Article  CAS  PubMed  Google Scholar 

  • Giaever G, Nislow C (2014) The yeast deletion collection: a decade of functional genomics. Genetics 197(2):451–465. doi:10.1534/genetics.114.161620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giaever G, Chu AM, Ni L, Connelly C, Riles L, Veronneau S, Dow S, Lucau-Danila A, Anderson K, Andre B, Arkin AP, Astromoff A, El-Bakkoury M, Bangham R, Benito R, Brachat S, Campanaro S, Curtiss M, Davis K, Deutschbauer A, Entian KD, Flaherty P, Foury F, Garfinkel DJ, Gerstein M, Gotte D, Guldener U, Hegemann JH, Hempel S, Herman Z, Jaramillo DF, Kelly DE, Kelly SL, Kotter P, LaBonte D, Lamb DC, Lan N, Liang H, Liao H, Liu L, Luo C, Lussier M, Mao R, Menard P, Ooi SL, Revuelta JL, Roberts CJ, Rose M, Ross-Macdonald P, Scherens B, Schimmack G, Shafer B, Shoemaker DD, Sookhai-Mahadeo S, Storms RK, Strathern JN, Valle G, Voet M, Volckaert G, Wang CY, Ward TR, Wilhelmy J, Winzeler EA, Yang Y, Yen G, Youngman E, Yu K, Bussey H, Boeke JD, Snyder M, Philippsen P, Davis RW, Johnston M (2002) Functional profiling of the Saccharomyces cerevisiae genome. Nature 418(6896):387–391

    Article  CAS  PubMed  Google Scholar 

  • Giaever G, Flaherty P, Kumm J, Proctor M, Nislow C, Jaramillo DF, Chu AM, Jordan MI, Arkin AP, Davis RW (2004) Chemogenomic profiling: identifying the functional interactions of small molecules in yeast. Proc Natl Acad Sci U S A 101(3):793–798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gimeno CJ, Ljungdahl PO, Styles CA, Fink GR (1992) Unipolar cell divisions in the yeast S. cerevisiae lead to filamentous growth: regulation by starvation and RAS. Cell 68(6):1077–1090

    Article  CAS  PubMed  Google Scholar 

  • Goffeau A, Barrell BG, Bussey H, Davis RW, Dujon B, Feldmann H, Galibert F, Hoheisel JD, Jacq C, Johnston M, Louis EJ, Mewes HW, Murakami Y, Philippsen P, Tettelin H, Oliver SG (1996) Life with 6000 genes. Science 274(5287):546, 563–547

    Google Scholar 

  • Golin J, Ambudkar SV, Gottesman MM, Habib AD, Sczepanski J, Ziccardi W, May L (2003) Studies with novel Pdr5p substrates demonstrate a strong size dependence for xenobiotic efflux. J Biol Chem 278(8):5963–5969. doi:10.1074/jbc.M210908200

    Article  CAS  PubMed  Google Scholar 

  • Golin J, Ambudkar SV, May L (2007) The yeast Pdr5p multidrug transporter: how does it recognize so many substrates? Biochem Biophys Res Commun 356(1):1–5. doi:10.1016/j.bbrc.2007.02.011

    Article  CAS  PubMed  Google Scholar 

  • Hanway D, Chin JK, Xia G, Oshiro G, Winzeler EA, Romesberg FE (2002) Previously uncharacterized genes in the UV- and MMS-induced DNA damage response in yeast. Proc Natl Acad Sci U S A 99(16):10605–10610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hawkesworth D (2001) The magnitude of fungal diversity: the 1.5 million species estimate revisited. Mycol Res 109:1422–1432

    Article  Google Scholar 

  • Hayama K, Ishibashi H, Ishijima SA, Niimi K, Tansho S, Ono Y, Monk BC, Holmes AR, Harding DR, Cannon RD, Abe S (2012) A D-octapeptide drug efflux pump inhibitor acts synergistically with azoles in a murine oral candidiasis infection model. FEMS Microbiol Lett 328(2):130–137. doi:10.1111/j.1574-6968.2011.02490.x

    Article  CAS  PubMed  Google Scholar 

  • Healey KR, Zhao Y, Perez WB, Lockhart SR, Sobel JD, Farmakiotis D, Kontoyiannis DP, Sanglard D, Taj-Aldeen SJ, Alexander BD, Jimenez-Ortigosa C, Shor E, Perlin DS (2016) Prevalent mutator genotype identified in fungal pathogen Candida glabrata promotes multi-drug resistance. Nat Commun 7:11128. doi:10.1038/ncomms11128

    Article  CAS  PubMed  Google Scholar 

  • Hector RF, Bierer DE (2011) New beta-glucan inhibitors as antifungal drugs. Expert Opin Ther Pat 21(10):1597–1610. doi:10.1517/13543776.2011.603899

    Article  CAS  PubMed  Google Scholar 

  • Heitman J (2005) Cell biology. A fungal Achilles’ heel. Science 309(5744):2175–2176

    Article  CAS  PubMed  Google Scholar 

  • Higgins CF (2001) ABC transporters: physiology, structure and mechanism—an overview. Res Microbiol 152(3–4):205–210

    Article  CAS  PubMed  Google Scholar 

  • Higgins CF, Linton KJ (2004) The ATP switch model for ABC transporters. Nat Struct Mol Biol 11(10):918–926

    Article  CAS  PubMed  Google Scholar 

  • Hiller D, Sanglard D, Morschhauser J (2006) Overexpression of the MDR1 gene is sufficient to confer increased resistance to toxic compounds in Candida albicans. Antimicrob Agents Chemother 50(4):1365–1371. doi:10.1128/AAC.50.4.1365-1371.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hiraga K, Yamamoto S, Fukuda H, Hamanaka N, Oda K (2005) Enniatin has a new function as an inhibitor of Pdr5p, one of the ABC transporters in Saccharomyces cerevisiae. Biochem Biophys Res Commun 328(4):1119–1125. doi:10.1016/j.bbrc.2005.01.075

    Article  CAS  PubMed  Google Scholar 

  • Holmes AR, Tsao S, Ong SW, Lamping E, Niimi K, Monk BC, Niimi M, Kaneko A, Holland BR, Schmid J, Cannon RD (2006) Heterozygosity and functional allelic variation in the Candida albicans efflux pump genes CDR1 and CDR2. Mol Microbiol 62(1):170–186

    Article  CAS  PubMed  Google Scholar 

  • Holmes AR, Lin YH, Niimi K, Lamping E, Keniya M, Niimi M, Tanabe K, Monk BC, Cannon RD (2008) ABC transporter Cdr1p contributes more than Cdr2p does to fluconazole efflux in fluconazole-resistant Candida albicans clinical isolates. Antimicrob Agents Chemother 52(11):3851–3862. doi:10.1128/AAC.00463-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Holmes AR, Keniya MV, Ivnitski-Steele I, Monk BC, Lamping E, Sklar LA, Cannon RD (2012) The monoamine oxidase A inhibitor clorgyline is a broad-spectrum inhibitor of fungal ABC and MFS transporter efflux pump activities which reverses the azole resistance of Candida albicans and Candida glabrata clinical isolates. Antimicrob Agents Chemother 56(3):1508–1515. doi:10.1128/AAC.05706-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hull CM, Raisner RM, Johnson AD (2000) Evidence for mating of the “asexual” yeast Candida albicans in a mammalian host. Science 289(5477):307–310

    Article  CAS  PubMed  Google Scholar 

  • Imoto S, Savoie CJ, Aburatani S, Kim S, Tashiro K, Kuhara S, Miyano S (2003) Use of gene networks for identifying and validating drug targets. J Bioinform Comput Biol 1(3):459–474

    Article  CAS  PubMed  Google Scholar 

  • Inoue SB, Takewaki N, Takasuka T, Mio T, Adachi M, Fujii Y, Miyamoto C, Arisawa M, Furuichi Y, Watanabe T (1995) Characterization and gene cloning of 1,3-beta-D-glucan synthase from Saccharomyces cerevisiae. Eur J Biochem 231(3):845–854

    Article  CAS  PubMed  Google Scholar 

  • Ivnitski-Steele I, Holmes AR, Lamping E, Monk BC, Cannon RD, Sklar LA (2009) Identification of Nile red as a fluorescent substrate of the Saccharomyces cerevisiae ATP-binding cassette transporters Cdr1p and Cdr2p and the major facilitator superfamily transporter Mdr1p. Anal Biochem 394(1):87–91. doi:10.1016/j.ab.2009.07.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Izumikawa K, Kakeya H, Tsai HF, Grimberg B, Bennett JE (2003) Function of Candida glabrata ABC transporter gene, PDH1. Yeast 20(3):249–261

    Article  CAS  PubMed  Google Scholar 

  • Jansen G, Lee AY, Epp E, Fredette A, Surprenant J, Harcus D, Scott M, Tan E, Nishimura T, Whiteway M, Hallett M, Thomas DY (2009) Chemogenomic profiling predicts antifungal synergies. Mol Syst Biol 5:338. doi:10.1038/msb.2009.95

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jasinski M, Ducos E, Martinoia E, Boutry M (2003) The ATP-binding cassette transporters: structure, function, and gene family comparison between rice and Arabidopsis. Plant Physiol 131(3):1169–1177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jensen LJ, Bork P (2008) Biochemistry. Not comparable, but complementary. Science 322(5898):56–57. doi:10.1126/science.1164801

  • Jones PM, George AM (2004) The ABC transporter structure and mechanism: perspectives on recent research. Cell Mol Life Sci 61(6):682–699

    Article  CAS  PubMed  Google Scholar 

  • Karababa M, Valentino E, Pardini G, Coste AT, Bille J, Sanglard D (2006) CRZ1, a target of the calcineurin pathway in Candida albicans. Mol Microbiol 59(5):1429–1451

    Article  CAS  PubMed  Google Scholar 

  • Katiyar SK, Edlind TD (2001) Identification and expression of multidrug resistance-related ABC transporter genes in Candida krusei. Med Mycol 39(1):109–116

    Article  CAS  PubMed  Google Scholar 

  • Katzmann DJ, Hallstrom TC, Mahe Y, Moye-Rowley WS (1996) Multiple Pdr1p/Pdr3p binding sites are essential for normal expression of the ATP binding cassette transporter protein-encoding gene PDR5. J Biol Chem 271(38):23049–23054

    Article  CAS  PubMed  Google Scholar 

  • Keniya MV, Cannon RD, Nguyen A, Tyndall JD, Monk BC (2013) Heterologous expression of Candida albicans Pma1p in Saccharomyces cerevisiae. FEMS Yeast Res 13(3):302–311. doi:10.1111/1567-1364.12035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Keniya MV, Fleischer E, Klinger A, Cannon RD, Monk BC (2015) Inhibitors of the Candida albicans major facilitator superfamily transporter Mdr1p responsible for fluconazole resistance. PLoS ONE 10(5):e0126350. doi:10.1371/journal.pone.0126350

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kim J, Wu S, Tomasiak TM, Mergel C, Winter MB, Stiller SB, Robles-Colmanares Y, Stroud RM, Tampe R, Craik CS, Cheng Y (2015) Subnanometre-resolution electron cryomicroscopy structure of a heterodimeric ABC exporter. Nature 517(7534):396–400. doi:10.1038/nature13872

    Article  CAS  PubMed  Google Scholar 

  • Kolaczkowski M, van der Rest M, Cybularz-Kolaczkowska A, Soumillion JP, Konings WN, Goffeau A (1996) Anticancer drugs, ionophoric peptides, and steroids as substrates of the yeast multidrug transporter Pdr5p. J Biol Chem 271(49):31543–31548

    Article  CAS  PubMed  Google Scholar 

  • Kolaczkowski M, Kolaczowska A, Luczynski J, Witek S, Goffeau A (1998) In vivo characterization of the drug resistance profile of the major ABC transporters and other components of the yeast pleiotropic drug resistance network. Microb Drug Resist 4(3):143–158. doi:10.1089/mdr.1998.4.143

    Article  CAS  PubMed  Google Scholar 

  • Kolaczkowski M, Michalak K, Motohashi N (2003) Phenothiazines as potent modulators of yeast multidrug resistance. Int J Antimicrob Agents 22(3):279–283

    Article  CAS  PubMed  Google Scholar 

  • Kolaczkowski M, Kolaczkowska A, Motohashi N, Michalak K (2009) New high-throughput screening assay to reveal similarities and differences in inhibitory sensitivities of multidrug ATP-binding cassette transporters. Antimicrob Agents Chemother 53(4):1516–1527. doi:10.1128/AAC.00956-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lacka I, Konieczny MT, Bulakowska A, Kodedova M, Gaskova D, Maurya IK, Prasad R, Milewski S (2015) Chemosensitization of multidrug resistant Candida albicans by the oxathiolone fused chalcone derivatives. Front Microbiol 6:783. doi:10.3389/fmicb.2015.00783

    Article  PubMed  PubMed Central  Google Scholar 

  • Lamping E, Monk BC, Niimi K, Holmes AR, Tsao S, Tanabe K, Niimi M, Uehara Y, Cannon RD (2007) Characterization of three classes of membrane proteins involved in fungal azole resistance by functional hyperexpression in Saccharomyces cerevisiae. Eukaryot Cell 6(7):1150–1165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lamping E, Ranchod A, Nakamura K, Tyndall JD, Niimi K, Holmes AR, Niimi M, Cannon RD (2009) Abc1p is a multidrug efflux transporter that tips the balance in favor of innate azole resistance in Candida krusei. Antimicrob Agents Chemother 53(2):354–369. doi:10.1128/AAC.01095-08

    Article  CAS  PubMed  Google Scholar 

  • Lamping E, Baret PV, Holmes AR, Monk BC, Goffeau A, Cannon RD (2010) Fungal PDR transporters: phylogeny, topology, motifs and function. Fungal Genet Biol 47(2):127–142. doi:10.1016/j.fgb.2009.10.007

    Article  CAS  PubMed  Google Scholar 

  • Lee MD, Galazzo JL, Staley AL, Lee JC, Warren MS, Fuernkranz H, Chamberland S, Lomovskaya O, Miller GH (2001) Microbial fermentation-derived inhibitors of efflux-pump-mediated drug resistance. Farmaco 56(1–2):81–85

    Article  CAS  PubMed  Google Scholar 

  • Lee AY, St Onge RP, Proctor MJ, Wallace IM, Nile AH, Spagnuolo PA, Jitkova Y, Gronda M, Wu Y, Kim MK, Cheung-Ong K, Torres NP, Spear ED, Han MK, Schlecht U, Suresh S, Duby G, Heisler LE, Surendra A, Fung E, Urbanus ML, Gebbia M, Lissina E, Miranda M, Chiang JH, Aparicio AM, Zeghouf M, Davis RW, Cherfils J, Boutry M, Kaiser CA, Cummins CL, Trimble WS, Brown GW, Schimmer AD, Bankaitis VA, Nislow C, Bader GD, Giaever G (2014) Mapping the cellular response to small molecules using chemogenomic fitness signatures. Science 344(6180):208–211. doi:10.1126/science.1250217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee JY, Kinch LN, Borek DM, Wang J, Wang J, Urbatsch IL, Xie XS, Grishin NV, Cohen JC, Otwinowski Z, Hobbs HH, Rosenbaum DM (2016) Crystal structure of the human sterol transporter ABCG5/ABCG8. Nature 533(7604):561–564. doi:10.1038/nature17666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li XC, Jacob MR, Ding Y, Agarwal AK, Smillie TJ, Khan SI, Nagle DG, Ferreira D, Clark AM (2006) Capisterones A and B, which enhance fluconazole activity in Saccharomyces cerevisiae, from the marine green alga Penicillus capitus. J Nat Prod 69(4):542–546. doi:10.1021/np050396y

  • Limtrakul P, Anuchapreeda S, Buddhasukh D (2004) Modulation of human multidrug-resistance MDR-1 gene by natural curcuminoids. BMC Cancer 4:13. doi:10.1186/1471-2407-4-13

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu M, Healy MD, Dougherty BA, Esposito KM, Maurice TC, Mazzucco CE, Bruccoleri RE, Davison DB, Frosco M, Barrett JF, Wang YK (2006) Conserved fungal genes as potential targets for broad-spectrum antifungal drug discovery. Eukaryot Cell 5(4):638–649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu XL, Tee HW, Go ML (2008) Functionalized chalcones as selective inhibitors of P-glycoprotein and breast cancer resistance protein. Bioorg Med Chem 16(1):171–180. doi:10.1016/j.bmc.2007.10.006

    Article  CAS  PubMed  Google Scholar 

  • Liu M, Zeng R, Zhang L, Li D, Lv G, Shen Y, Zheng H, Zhang Q, Zhao J, Zheng N, Liu W (2015) Multiple cyp51A-based mechanisms identified in azole-resistant isolates of Aspergillus fumigatus from China. Antimicrob Agents Chemother 59(7):4321–4325. doi:10.1128/AAC.00003-15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lo HJ, Tseng KY, Kao YY, Tsao MY, Lo HL, Yang YL (2015) Cph1p negatively regulates MDR1 involved in drug resistance in Candida albicans. Int J Antimicrob Agents 45(6):617–621. doi:10.1016/j.ijantimicag.2015.01.017

    Article  CAS  PubMed  Google Scholar 

  • Loftus BJ, Fung E, Roncaglia P, Rowley D, Amedeo P, Bruno D, Vamathevan J, Miranda M, Anderson IJ, Fraser JA, Allen JE, Bosdet IE, Brent MR, Chiu R, Doering TL, Donlin MJ, D’Souza CA, Fox DS, Grinberg V, Fu J, Fukushima M, Haas BJ, Huang JC, Janbon G, Jones SJ, Koo HL, Krzywinski MI, Kwon-Chung JK, Lengeler KB, Maiti R, Marra MA, Marra RE, Mathewson CA, Mitchell TG, Pertea M, Riggs FR, Salzberg SL, Schein JE, Shvartsbeyn A, Shin H, Shumway M, Specht CA, Suh BB, Tenney A, Utterback TR, Wickes BL, Wortman JR, Wye NH, Kronstad JW, Lodge JK, Heitman J, Davis RW, Fraser CM, Hyman RW (2005) The genome of the basidiomycetous yeast and human pathogen Cryptococcus neoformans. Science 307(5713):1321–1324

    Article  PubMed  PubMed Central  Google Scholar 

  • Lohberger A, Coste AT, Sanglard D (2014) Distinct roles of Candida albicans drug resistance transcription factors TAC1, MRR1, and UPC2 in virulence. Eukaryot Cell 13(1):127–142. doi:10.1128/EC.00245-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lomovskaya O, Bostian KA (2006) Practical applications and feasibility of efflux pump inhibitors in the clinic—a vision for applied use. Biochem Pharmacol 71(7):910–918. doi:10.1016/j.bcp.2005.12.008

    Article  CAS  PubMed  Google Scholar 

  • Lum PY, Armour CD, Stepaniants SB, Cavet G, Wolf MK, Butler JS, Hinshaw JC, Garnier P, Prestwich GD, Leonardson A, Garrett-Engele P, Rush CM, Bard M, Schimmack G, Phillips JW, Roberts CJ, Shoemaker DD (2004) Discovering modes of action for therapeutic compounds using a genome-wide screen of yeast heterozygotes. Cell 116(1):121–137

    Article  CAS  PubMed  Google Scholar 

  • Maebashi K, Niimi M, Kudoh M, Fischer FJ, Makimura K, Niimi K, Piper RJ, Uchida K, Arisawa M, Cannon RD, Yamaguchi H (2001) Mechanisms of fluconazole resistance in Candida albicans isolates from Japanese AIDS patients. J Antimicrob Chemother 47(5):527–536

    Article  CAS  PubMed  Google Scholar 

  • Maki N, Dey S (2006) Biochemical and pharmacological properties of an allosteric modulator site of the human P-glycoprotein (ABCB1). Biochem Pharmacol 72(2):145–155. doi:10.1016/j.bcp.2006.04.008

    Article  CAS  PubMed  Google Scholar 

  • Mamnun YM, Pandjaitan R, Mahe Y, Delahodde A, Kuchler K (2002) The yeast zinc finger regulators Pdr1p and Pdr3p control pleiotropic drug resistance (PDR) as homo- and heterodimers in vivo. Mol Microbiol 46(5):1429–1440

    Article  CAS  PubMed  Google Scholar 

  • Mansfield BE, Oltean HN, Oliver BG, Hoot SJ, Leyde SE, Hedstrom L, White TC (2010) Azole drugs are imported by facilitated diffusion in Candida albicans and other pathogenic fungi. PLoS Pathog 6(9):e1001126. doi:10.1371/journal.ppat.1001126

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mathema B, Cross E, Dun E, Park S, Bedell J, Slade B, Williams M, Riley L, Chaturvedi V, Perlin DS (2001) Prevalence of vaginal colonization by drug-resistant Candida species in college-age women with previous exposure to over-the-counter azole antifungals. Clin Infect Dis 33(5):E23–27. doi:10.1086/322600

    Article  CAS  PubMed  Google Scholar 

  • Maurya IK, Thota CK, Verma SD, Sharma J, Rawal MK, Ravikumar B, Sen S, Chauhan N, Lynn AM, Chauhan VS, Prasad R (2013) Rationally designed transmembrane peptide mimics of the multidrug transporter protein Cdr1 act as antagonists to selectively block drug efflux and chemosensitize azole-resistant clinical isolates of Candida albicans. J Biol Chem 288(23):16775–16787. doi:10.1074/jbc.M113.467159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mellado E, Diaz-Guerra TM, Cuenca-Estrella M, Rodriguez-Tudela JL (2001) Identification of two different 14-alpha sterol demethylase-related genes (cyp51A and cyp51B) in Aspergillus fumigatus and other Aspergillus species. J Clin Microbiol 39(7):2431–2438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miyazaki H, Miyazaki Y, Geber A, Parkinson T, Hitchcock C, Falconer DJ, Ward DJ, Marsden K, Bennett JE (1998) Fluconazole resistance associated with drug efflux and increased transcription of a drug transporter gene, PDH1, in Candida glabrata. Antimicrob Agents Chemother 42(7):1695–1701

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mohammadi F, Hashemi SJ, Zoll J, Melchers WJ, Rafati H, Dehghan P, Rezaie S, Tolooe A, Tamadon Y, van der Lee HA, Verweij PE, Seyedmousavi S (2016) Quantitative analysis of single-nucleotide polymorphism for rapid detection of TR34/L98H- and TR46/Y121F/T289A-positive Aspergillus fumigatus isolates obtained from patients in Iran from 2010 to 2014. Antimicrob Agents Chemother 60(1):387–392. doi:10.1128/AAC.02326-15

    Article  CAS  Google Scholar 

  • Moitra K, Lou H, Dean M (2011) Multidrug efflux pumps and cancer stem cells: insights into multidrug resistance and therapeutic development. Clin Pharmacol Ther 89(4):491–502. doi:10.1038/clpt.2011.14

    Article  CAS  PubMed  Google Scholar 

  • Monk BC, Goffeau A (2008) Outwitting multidrug resistance to antifungals. Science 321(5887):367–369. doi:10.1126/science.1159746

    Article  CAS  PubMed  Google Scholar 

  • Monk BC, Harding DR (2005) Peptide motifs for cell-surface intervention: application to anti-infective and biopharmaceutical development. BioDrugs 19(4):261–278

    Article  CAS  PubMed  Google Scholar 

  • Monk BC, Niimi K, Lin S, Knight A, Kardos TB, Cannon RD, Parshot R, King A, Lun D, Harding DR (2005) Surface-active fungicidal D-peptide inhibitors of the plasma membrane proton pump that block azole resistance. Antimicrob Agents Chemother 49(1):57–70

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Monk BC, Tomasiak TM, Keniya MV, Huschmann FU, Tyndall JD, O’Connell JD 3rd, Cannon RD, McDonald JG, Rodriguez A, Finer-Moore JS, Stroud RM (2014) Architecture of a single membrane spanning cytochrome P450 suggests constraints that orient the catalytic domain relative to a bilayer. Proc Natl Acad Sci USA 111(10):3865–3870. doi:10.1073/pnas.1324245111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morio F, Loge C, Besse B, Hennequin C, Le Pape P (2010) Screening for amino acid substitutions in the Candida albicans Erg11 protein of azole-susceptible and azole-resistant clinical isolates: new substitutions and a review of the literature. Diagn Microbiol Infect Dis 66(4):373–384. doi:10.1016/j.diagmicrobio.2009.11.006

    Article  CAS  PubMed  Google Scholar 

  • Morschhauser J (2016) The development of fluconazole resistance in Candida albicans—an example of microevolution of a fungal pathogen. J Microbiol 54(3):192–201. doi:10.1007/s12275-016-5628-4

    Article  PubMed  CAS  Google Scholar 

  • Morschhauser J, Barker KS, Liu TT, Bla BWJ, Homayouni R, Rogers PD (2007) The transcription factor Mrr1p controls expression of the MDR1 efflux pump and mediates multidrug resistance in Candida albicans. PLoS Pathog 3(11):e164. doi:10.1371/journal.ppat.0030164

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Nakamura K, Niimi M, Niimi K, Holmes AR, Yates JE, Decottignies A, Monk BC, Goffeau A, Cannon RD (2001) Functional expression of Candida albicans drug efflux pump Cdr1p in a Saccharomyces cerevisiae strain deficient in membrane transporters. Antimicrob Agents Chemother 45(12):3366–3374. doi:10.1128/AAC.45.12.3366-3374.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nascimento AM, Goldman GH, Park S, Marras SA, Delmas G, Oza U, Lolans K, Dudley MN, Mann PA, Perlin DS (2003) Multiple resistance mechanisms among Aspergillus fumigatus mutants with high-level resistance to itraconazole. Antimicrob Agents Chemother 47(5):1719–1726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nierman WC, Pain A, Anderson MJ, Wortman JR, Kim HS, Arroyo J, Berriman M, Abe K, Archer DB, Bermejo C, Bennett J, Bowyer P, Chen D, Collins M, Coulsen R, Davies R, Dyer PS, Farman M, Fedorova N, Fedorova N, Feldblyum TV, Fischer R, Fosker N, Fraser A, Garcia JL, Garcia MJ, Goble A, Goldman GH, Gomi K, Griffith-Jones S, Gwilliam R, Haas B, Haas H, Harris D, Horiuchi H, Huang J, Humphray S, Jimenez J, Keller N, Khouri H, Kitamoto K, Kobayashi T, Konzack S, Kulkarni R, Kumagai T, Lafon A, Latge JP, Li W, Lord A, Lu C, Majoros WH, May GS, Miller BL, Mohamoud Y, Molina M, Monod M, Mouyna I, Mulligan S, Murphy L, O’Neil S, Paulsen I, Penalva MA, Pertea M, Price C, Pritchard BL, Quail MA, Rabbinowitsch E, Rawlins N, Rajandream MA, Reichard U, Renauld H, Robson GD, Rodriguez de Cordoba S, Rodriguez-Pena JM, Ronning CM, Rutter S, Salzberg SL, Sanchez M, Sanchez-Ferrero JC, Saunders D, Seeger K, Squares R, Squares S, Takeuchi M, Tekaia F, Turner G, Vazquez de Aldana CR, Weidman J, White O, Woodward J, Yu JH, Fraser C, Galagan JE, Asai K, Machida M, Hall N, Barrell B, Denning DW (2005) Genomic sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus. Nature 438(7071):1151–1156

    Article  CAS  PubMed  Google Scholar 

  • Niimi M, Nagai Y, Niimi K, Wada S, Cannon RD, Uehara Y, Monk BC (2002) Identification of two proteins induced by exposure of the pathogenic fungus Candida glabrata to fluconazole. J Chromatogr B Analyt Technol Biomed Life Sci 782(1–2):245–252

    Article  CAS  PubMed  Google Scholar 

  • Niimi K, Harding DR, Parshot R, King A, Lun DJ, Decottignies A, Niimi M, Lin S, Cannon RD, Goffeau A, Monk BC (2004) Chemosensitization of fluconazole resistance in Saccharomyces cerevisiae and pathogenic fungi by a D-octapeptide derivative. Antimicrob Agents Chemother 48(4):1256–1271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Niimi K, Maki K, Ikeda F, Holmes AR, Lamping E, Niimi M, Monk BC, Cannon RD (2006) Overexpression of Candida albicans CDR1, CDR2, or MDR1 does not produce significant changes in echinocandin susceptibility. Antimicrob Agents Chemother 50(4):1148–1155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Niimi K, Harding DR, Holmes AR, Lamping E, Niimi M, Tyndall JD, Cannon RD, Monk BC (2012) Specific interactions between the Candida albicans ABC transporter Cdr1p ectodomain and a D-octapeptide derivative inhibitor. Mol Microbiol 85(4):747–767. doi:10.1111/j.1365-2958.2012.08140.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nim S, Rawal MK, Prasad R (2014) FK520 interacts with the discrete intrahelical amino acids of multidrug transporter Cdr1 protein and acts as antagonist to selectively chemosensitize azole-resistant clinical isolates of Candida albicans. FEMS Yeast Res 14(4):624–632. doi:10.1111/1567-1364.12149

    Article  CAS  PubMed  Google Scholar 

  • Nim S, Monico A, Rawal MK, Duarte N, Prasad R, Di Pietro A, Ferreira MU (2016) Overcoming multidrug resistance in Candida albicans: macrocyclic diterpenes from euphorbia species as potent inhibitors of drug efflux pumps. Planta Med. doi:10.1055/s-0042-106169

    PubMed  Google Scholar 

  • Nishikawa JL, Boeszoermenyi A, Vale-Silva LA, Torelli R, Posteraro B, Sohn YJ, Ji F, Gelev V, Sanglard D, Sanguinetti M, Sadreyev RI, Mukherjee G, Bhyravabhotla J, Buhrlage SJ, Gray NS, Wagner G, Naar AM, Arthanari H (2016) Inhibiting fungal multidrug resistance by disrupting an activator-Mediator interaction. Nature 530(7591):485–489. doi:10.1038/nature16963

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • O’Brien HE, Parrent JL, Jackson JA, Moncalvo JM, Vilgalys R (2005) Fungal community analysis by large-scale sequencing of environmental samples. Appl Environ Microbiol 71(9):5544–5550. doi:10.1128/AEM.71.9.5544-5550.2005

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Onishi J, Meinz M, Thompson J, Curotto J, Dreikorn S, Rosenbach M, Douglas C, Abruzzo G, Flattery A, Kong L, Cabello A, Vicente F, Pelaez F, Diez MT, Martin I, Bills G, Giacobbe R, Dombrowski A, Schwartz R, Morris S, Harris G, Tsipouras A, Wilson K, Kurtz MB (2000) Discovery of novel antifungal (1,3)-beta-D-glucan synthase inhibitors. Antimicrob Agents Chemother 44(2):368–377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Onyewu C, Wormley FL Jr, Perfect JR, Heitman J (2004) The calcineurin target, Crz1, functions in azole tolerance but is not required for virulence of Candida albicans. Infect Immun 72(12):7330–7333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Palecek SP, Parikh AS, Kron SJ (2002) Sensing, signalling and integrating physical processes during Saccharomyces cerevisiae invasive and filamentous growth. Microbiology 148(Pt 4):893–907

    Article  CAS  PubMed  Google Scholar 

  • Parker JL, Newstead S (2014) Molecular basis of nitrate uptake by the plant nitrate transporter NRT1.1. Nature 507(7490):68–72. doi:10.1038/nature13116

  • Parker JE, Warrilow AG, Price CL, Mullins JG, Kelly DE, Kelly SL (2014) Resistance to antifungals that target CYP51. J Chem Biol 7(4):143–161. doi:10.1007/s12154-014-0121-1

    Article  PubMed  PubMed Central  Google Scholar 

  • Parsons AB, Brost RL, Ding H, Li Z, Zhang C, Sheikh B, Brown GW, Kane PM, Hughes TR, Boone C (2004) Integration of chemical-genetic and genetic interaction data links bioactive compounds to cellular target pathways. Nat Biotechnol 22(1):62–69

    Article  CAS  PubMed  Google Scholar 

  • Parsons AB, Bussey H, Boone C (2006) Functional genomic approaches to fungal pathogenesis, drug target validation, and antifungal drug discovery. In: Heitman Jea (ed) Molecular principles of fungal pathogenesis

    Google Scholar 

  • Paul S, Moye-Rowley WS (2014) Multidrug resistance in fungi: regulation of transporter-encoding gene expression. Front Physiol 5:143. doi:10.3389/fphys.2014.00143

    Article  PubMed  PubMed Central  Google Scholar 

  • Paulsen IT, Skurray RA (1993) Topology, structure and evolution of two families of proteins involved in antibiotic and antiseptic resistance in eukaryotes and prokaryotes—an analysis. Gene 124(1):1–11

    Article  CAS  PubMed  Google Scholar 

  • Paumi CM, Chuk M, Snider J, Stagljar I, Michaelis S (2009) ABC transporters in Saccharomyces cerevisiae and their interactors: new technology advances the biology of the ABCC (MRP) subfamily. Microbiol Mol Biol Rev 73(4):577–593. doi:10.1128/MMBR.00020-09

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Payne DJ, Gwynn MN, Holmes DJ, Pompliano DL (2007) Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat Rev Drug Discov 6(1):29–40

    Article  CAS  PubMed  Google Scholar 

  • Pedersen BP, Kumar H, Waight AB, Risenmay AJ, Roe-Zurz Z, Chau BH, Schlessinger A, Bonomi M, Harries W, Sali A, Johri AK, Stroud RM (2013) Crystal structure of a eukaryotic phosphate transporter. Nature 496(7446):533–536. doi:10.1038/nature12042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perea S, Lopez-Ribot JL, Kirkpatrick WR, McAtee RK, Santillan RA, Martinez M, Calabrese D, Sanglard D, Patterson TF (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(10):2676–2684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pfaller MA (2012) Antifungal drug resistance: mechanisms, epidemiology, and consequences for treatment. Am J Med 125(1 Suppl):S3–13. doi:10.1016/j.amjmed.2011.11.001

    Article  CAS  PubMed  Google Scholar 

  • Pfaller MA, Diekema DJ (2007) Epidemiology of invasive candidiasis: a persistent public health problem. Clin Microbiol Rev 20(1):133–163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pfaller MA, Diekema DJ (2010) Epidemiology of invasive mycoses in North America. Crit Rev Microbiol 36(1):1–53. doi:10.3109/10408410903241444

    Article  PubMed  Google Scholar 

  • Piddock LJ (2006) Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria. Clin Microbiol Rev 19(2):382–402. doi:10.1128/CMR.19.2.382-402.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Posteraro B, Sanguinetti M, Sanglard D, La Sorda M, Boccia S, Romano L, Morace G, Fadda G (2003) Identification and characterization of a Cryptococcus neoformans ATP binding cassette (ABC) transporter-encoding gene, CnAFR1, involved in the resistance to fluconazole. Mol Microbiol 47(2):357–371

    Article  CAS  PubMed  Google Scholar 

  • Prasad R, Goffeau A (2012) Yeast ATP-binding cassette transporters conferring multidrug resistance. Annu Rev Microbiol 66:39–63. doi:10.1146/annurev-micro-092611-150111

    Article  CAS  PubMed  Google Scholar 

  • Prasad R, Rawal MK (2014) Efflux pump proteins in antifungal resistance. Front Pharmacol 5:202. doi:10.3389/fphar.2014.00202

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Prasad R, De Wergifosse P, Goffeau A, Balzi E (1995) Molecular cloning and characterization of a novel gene of Candida albicans, CDR1, conferring multiple resistance to drugs and antifungals. Curr Genet 27(4):320–329

    Article  CAS  PubMed  Google Scholar 

  • Quistgaard EM, Low C, Guettou F, Nordlund P (2016) Understanding transport by the major facilitator superfamily (MFS): structures pave the way. Nat Rev Mol Cell Biol 17(2):123–132. doi:10.1038/nrm.2015.25

    Article  CAS  PubMed  Google Scholar 

  • Ramage G, Bachmann S, Patterson TF, Wickes BL, Lopez-Ribot JL (2002) Investigation of multidrug efflux pumps in relation to fluconazole resistance in Candida albicans biofilms. J Antimicrob Chemother 49(6):973–980

    Article  CAS  PubMed  Google Scholar 

  • Ramage G, Martinez JP, Lopez-Ribot JL (2006) Candida biofilms on implanted biomaterials: a clinically significant problem. FEMS Yeast Res 6(7):979–986

    Article  CAS  PubMed  Google Scholar 

  • Rawal MK, Khan MF, Kapoor K, Goyal N, Sen S, Saxena AK, Lynn AM, Tyndall JD, Monk BC, Cannon RD, Komath SS, Prasad R (2013) Insight into pleiotropic drug resistance ATP-binding cassette pump drug transport through mutagenesis of Cdr1p transmembrane domains. J Biol Chem 288(34):24480–24493. doi:10.1074/jbc.M113.488353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rawal MK, Shokoohinia Y, Chianese G, Zolfaghari B, Appendino G, Taglialatela-Scafati O, Prasad R, Di Pietro A (2014) Jatrophanes from Euphorbia squamosa as potent inhibitors of Candida albicans multidrug transporters. J Nat Prod 77(12):2700–2706. doi:10.1021/np500756z

    Article  CAS  PubMed  Google Scholar 

  • Redhu AK, Shah AH, Prasad R (2016) MFS transporters of Candida species and their role in clinical drug resistance. FEMS Yeast Research 16. doi:10.1093/fensyr/fow043

  • Rees DC, Johnson E, Lewinson O (2009) ABC transporters: the power to change. Nat Rev Mol Cell Biol 10(3):218–227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reynolds TB, Fink GR (2001) Bakers’ yeast, a model for fungal biofilm formation. Science 291(5505):878–881

    Article  CAS  PubMed  Google Scholar 

  • Ricardo E, Costa-de-Oliveira S, Dias AS, Guerra J, Rodrigues AG, Pina-Vaz C (2009) Ibuprofen reverts antifungal resistance on Candida albicans showing overexpression of CDR genes. FEMS Yeast Res 9(4):618–625. doi:10.1111/j.1567-1364.2009.00504.x

    Article  CAS  PubMed  Google Scholar 

  • Riggle PJ, Kumamoto CA (2006) Transcriptional regulation of MDR1, encoding a drug efflux determinant, in fluconazole-resistant Candida albicans strains through an Mcm1p binding site. Eukaryot Cell 5(12):1957–1968. doi:10.1128/EC.00243-06

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roemer T, Jiang B, Davison J, Ketela T, Veillette K, Breton A, Tandia F, Linteau A, Sillaots S, Marta C, Martel N, Veronneau S, Lemieux S, Kauffman S, Becker J, Storms R, Boone C, Bussey H (2003) Large-scale essential gene identification in Candida albicans and applications to antifungal drug discovery. Mol Microbiol 50(1):167–181

    Article  CAS  PubMed  Google Scholar 

  • Rogers PD, Barker KS (2003) Genome-wide expression profile analysis reveals coordinately regulated genes associated with stepwise acquisition of azole resistance in Candida albicans clinical isolates. Antimicrob Agents Chemother 47(4):1220–1227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rognon B, Kozovska Z, Coste AT, Pardini G, Sanglard D (2006) Identification of promoter elements responsible for the regulation of MDR1 from Candida albicans, a major facilitator transporter involved in azole resistance. Microbiology 152(Pt 12):3701–3722. doi:10.1099/mic.0.29277-0

    Article  CAS  PubMed  Google Scholar 

  • Rustad TR, Stevens DA, Pfaller MA, White TC (2002) Homozygosity at the Candida albicans MTL locus associated with azole resistance. Microbiology 148(Pt 4):1061–1072. doi:10.1099/00221287-148-4-1061

    Article  CAS  PubMed  Google Scholar 

  • Rutledge RM, Esser L, Ma J, Xia D (2011) Toward understanding the mechanism of action of the yeast multidrug resistance transporter Pdr5p: a molecular modeling study. J Struct Biol 173(2):333–344. doi:10.1016/j.jsb.2010.10.012

    Article  CAS  PubMed  Google Scholar 

  • Sagatova AA, Keniya MV, Wilson RK, Monk BC, Tyndall JD (2015) Structural insights into binding of the antifungal drug fluconazole to Saccharomyces cerevisiae lanosterol 14alpha-demethylase. Antimicrob Agents Chemother 59(8):4982–4989. doi:10.1128/AAC.00925-15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sagatova AA, Keniya MV, Wilson RK, Sabherwal M, Tyndall JD, Monk BC (2016) Triazole resistance mediated by mutations of a conserved active site tyrosine in fungal lanosterol 14alpha-demethylase. Sci Rep 6:26213. doi:10.1038/srep26213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saini P, Prasad T, Gaur NA, Shukla S, Jha S, Komath SS, Khan LA, Haq QM, Prasad R (2005) Alanine scanning of transmembrane helix 11 of Cdr1p ABC antifungal efflux pump of Candida albicans: identification of amino acid residues critical for drug efflux. J Antimicrob Chemother 56(1):77–86. doi:10.1093/jac/dki183

    Article  CAS  PubMed  Google Scholar 

  • Sanchez-Leon E, Riquelme M (2015) Live imaging of beta-1,3-glucan synthase FKS-1 in Neurospora crassa hyphae. Fungal Genet Biol 82:104–107. doi:10.1016/j.fgb.2015.07.001

    Article  CAS  PubMed  Google Scholar 

  • Sanglard D, Bille J (2002) Current understanding of the modes of action of and resistance mechanisms to conventional and emerging antifungal agents for treatment of Candida infections. In: Calderone RA (ed) Candida and Candidiasis. ASM Press, Washington, DC, pp 349–383

    Google Scholar 

  • Sanglard D, Kuchler K, Ischer F, Pagani JL, Monod M, Bille J (1995) Mechanisms of resistance to azole antifungal agents in Candida albicans isolates from AIDS patients involve specific multidrug transporters. Antimicrob Agents Chemother 39(11):2378–2386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sanglard D, Ischer F, Koymans L, Bille J (1998) Amino acid substitutions in the cytochrome P-450 lanosterol 14alpha-demethylase (CYP51A1) from azole-resistant Candida albicans clinical isolates contribute to resistance to azole antifungal agents. Antimicrob Agents Chemother 42(2):241–253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sanglard D, Ischer F, Calabrese D, Majcherczyk PA, Bille J (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(11):2753–2765

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sanglard D, Ischer F, Bille J (2001) Role of ATP-binding-cassette transporter genes in high-frequency acquisition of resistance to azole antifungals in Candida glabrata. Antimicrob Agents Chemother 45(4):1174–1183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sanglard D, Ischer F, Marchetti O, Entenza J, Bille J (2003) Calcineurin A of Candida albicans: involvement in antifungal tolerance, cell morphogenesis and virulence. Mol Microbiol 48(4):959–976

    Article  CAS  PubMed  Google Scholar 

  • Sanguinetti M, Posteraro B, La Sorda M, Torelli R, Fiori B, Santangelo R, Delogu G, Fadda G (2006) Role of AFR1, an ABC transporter-encoding gene, in the in vivo response to fluconazole and virulence of Cryptococcus neoformans. Infect Immun 74(2):1352–1359

    Google Scholar 

  • Saraswathy M, Gong S (2013) Different strategies to overcome multidrug resistance in cancer. Biotechnol Adv 31(8):1397–1407. doi:10.1016/j.biotechadv.2013.06.004

    Article  CAS  PubMed  Google Scholar 

  • Sauna ZE, Bohn SS, Rutledge R, Dougherty MP, Cronin S, May L, Xia D, Ambudkar SV, Golin J (2008) Mutations define cross-talk between the N-terminal nucleotide-binding domain and transmembrane helix-2 of the yeast multidrug transporter Pdr5: possible conservation of a signaling interface for coupling ATP hydrolysis to drug transport. J Biol Chem 283(50):35010–35022. doi:10.1074/jbc.M806446200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schmid D, Ecker G, Kopp S, Hitzler M, Chiba P (1999) Structure-activity relationship studies of propafenone analogs based on P-glycoprotein ATPase activity measurements. Biochem Pharmacol 58(9):1447–1456

    Article  CAS  PubMed  Google Scholar 

  • Schubert S, Barker KS, Znaidi S, Schneider S, Dierolf F, Dunkel N, Aid M, Boucher G, Rogers PD, Raymond M, Morschhauser J (2011a) Regulation of efflux pump expression and drug resistance by the transcription factors Mrr1, Upc2, and Cap1 in Candida albicans. Antimicrob Agents Chemother 55(5):2212–2223. doi:10.1128/AAC.01343-10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schubert S, Popp C, Rogers PD, Morschhauser J (2011b) Functional dissection of a Candida albicans zinc cluster transcription factor, the multidrug resistance regulator Mrr1. Eukaryot Cell 10(8):1110–1121. doi:10.1128/EC.05100-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schumacher MA, Brennan RG (2003) Deciphering the molecular basis of multidrug recognition: crystal structures of the Staphlyococcus aureus multidrug binding transcription regulator QacR. Res Microbiol 154(2):69–77

    Article  CAS  PubMed  Google Scholar 

  • Selmecki A, Forche A, Berman J (2006) Aneuploidy and isochromosome formation in drug-resistant Candida albicans. Science 313(5785):367–370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seoighe C, Federspiel N, Jones T, Hansen N, Bivolarovic V, Surzycki R, Tamse R, Komp C, Huizar L, Davis RW, Scherer S, Tait E, Shaw DJ, Harris D, Murphy L, Oliver K, Taylor K, Rajandream MA, Barrell BG, Wolfe KH (2000) Prevalence of small inversions in yeast gene order evolution. Proc Natl Acad Sci U S A 97(26):14433–14437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shahi P, Moye-Rowley WS (2009) Coordinate control of lipid composition and drug transport activities is required for normal multidrug resistance in fungi. Biochim Biophys Acta 1794(5):852–859

    Article  CAS  PubMed  Google Scholar 

  • Sharma M, Prasad R (2011) The quorum-sensing molecule farnesol is a modulator of drug efflux mediated by ABC multidrug transporters and synergizes with drugs in Candida albicans. Antimicrob Agents Chemother 55(10):4834–4843. doi:10.1128/AAC.00344-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sharma M, Manoharlal R, Shukla S, Puri N, Prasad T, Ambudkar SV, Prasad R (2009) Curcumin modulates efflux mediated by yeast ABC multidrug transporters and is synergistic with antifungals. Antimicrob Agents Chemother 53(8):3256–3265. doi:10.1128/AAC.01497-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shedletzky E, Unger C, Delmer DP (1997) A microtiter-based fluorescence assay for (1,3)-beta-glucan synthases. Anal Biochem 249(1):88–93. doi:10.1006/abio.1997.2162

    Article  CAS  PubMed  Google Scholar 

  • Shields DC, Wolfe KH (1997) Accelerated evolution of sites undergoing mRNA editing in plant mitochondria and chloroplasts. Mol Biol Evol 14(3):344–349

    Article  CAS  PubMed  Google Scholar 

  • Shukla S, Sauna ZE, Prasad R, Ambudkar SV (2004) Disulfiram is a potent modulator of multidrug transporter Cdr1p of Candida albicans. Biochem Biophys Res Commun 322(2):520–525. doi:10.1016/j.bbrc.2004.07.151

    Article  CAS  PubMed  Google Scholar 

  • Shukla S, Rai V, Saini P, Banerjee D, Menon AK, Prasad R (2007) Candida drug resistance protein 1, a major multidrug ATP binding cassette transporter of Candida albicans, translocates fluorescent phospholipids in a reconstituted system. Biochemistry 46(43):12081–12090. doi:10.1021/bi700453e

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Silva LV, Sanguinetti M, Vandeputte P, Torelli R, Rochat B, Sanglard D (2013) Milbemycins: more than efflux inhibitors for fungal pathogens. Antimicrob Agents Chemother 57(2):873–886. doi:10.1128/AAC.02040-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Singh N, Perfect JR (2007) Immune reconstitution syndrome associated with opportunistic mycoses. Lancet Infect Dis 7(6):395–401. doi:10.1016/S1473-3099(07)70085-3

    Article  PubMed  Google Scholar 

  • Sionov E, Chang YC, Kwon-Chung KJ (2013) Azole heteroresistance in Cryptococcus neoformans: emergence of resistant clones with chromosomal disomy in the mouse brain during fluconazole treatment. Antimicrob Agents Chemother 57(10):5127–5130. doi:10.1128/AAC.00694-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sklar LA, Carter MB, Edwards BS (2007) Flow cytometry for drug discovery, receptor pharmacology and high-throughput screening. Curr Opin Pharmacol 7(5):527–534. doi:10.1016/j.coph.2007.06.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smriti KS, Dixit BL, Gupta CM, Milewski S, Prasad R (2002) ABC transporters Cdr1p, Cdr2p and Cdr3p of a human pathogen Candida albicans are general phospholipid translocators. Yeast 19(4):303–318. doi:10.1002/yea.818

    Article  CAS  PubMed  Google Scholar 

  • Snelders E, Huis In ‘t Veld RA, Rijs AJ, Kema GH, Melchers WJ, Verweij PE (2009) Possible environmental origin of resistance of Aspergillus fumigatus to medical triazoles. Appl Environ Microbiol 75(12):4053–4057. doi:10.1128/AEM.00231-09

  • Snelders E, van der Lee HA, Kuijpers J, Rijs AJ, Varga J, Samson RA, Mellado E, Donders AR, Melchers WJ, Verweij PE (2008) Emergence of azole resistance in Aspergillus fumigatus and spread of a single resistance mechanism. PLoS Med 5(11):e219. doi:10.1371/journal.pmed.0050219

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Snider J, Hanif A, Lee ME, Jin K, Yu AR, Graham C, Chuk M, Damjanovic D, Wierzbicka M, Tang P, Balderes D, Wong V, Jessulat M, Darowski KD, San Luis BJ, Shevelev I, Sturley SL, Boone C, Greenblatt JF, Zhang Z, Paumi CM, Babu M, Park HO, Michaelis S, Stagljar I (2013) Mapping the functional yeast ABC transporter interactome. Nat Chem Biol 9(9):565–572. doi:10.1038/nchembio.1293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spitzer M, Griffiths E, Blakely KM, Wildenhain J, Ejim L, Rossi L, De Pascale G, Curak J, Brown E, Tyers M, Wright GD (2011) Cross-species discovery of syncretic drug combinations that potentiate the antifungal fluconazole. Mol Syst Biol 7:499. doi:10.1038/msb.2011.31

    Article  PubMed  PubMed Central  Google Scholar 

  • Strouse JJ, Ivnitski-Steele I, Njus HM, Foutz TD, Yao T, Weiner WS, Schroeder CE, Simpson DS, Maki BE, Li K, Golden JE, Waller A, Evangelisti AM, Young SM, Perez D, Chavez SE, Garcia MJ, Ursu O, Fara DC, Bologa CG, Carter MB, Salas VM, Tegos GP, Oprea TI, Edwards BS, Larson RS, Aube J, Sklar LA (2010) Selective efflux inhibition of ATP-binding cassette sub-family G member 2. In: Probe reports from the NIH molecular libraries program, Bethesda (MD)

    Google Scholar 

  • Sun J, Bankston JR, Payandeh J, Hinds TR, Zagotta WN, Zheng N (2014) Crystal structure of the plant dual-affinity nitrate transporter NRT1.1. Nature 507(7490):73–77. doi:10.1038/nature13074

  • Suzuki K, Saito K, Tsujimura S, Nakayamada S, Yamaoka K, Sawamukai N, Iwata S, Nawata M, Nakano K, Tanaka Y (2010) Tacrolimus, a calcineurin inhibitor, overcomes treatment unresponsiveness mediated by P-glycoprotein on lymphocytes in refractory rheumatoid arthritis. J Rheumatol 37(3):512–520. doi:10.3899/jrheum.090048

    Article  CAS  PubMed  Google Scholar 

  • Taglicht D, Michaelis S (1998) Saccharomyces cerevisiae ABC proteins and their relevance to human health and disease. Methods Enzymol 292:130–162

    Article  CAS  PubMed  Google Scholar 

  • Tamay-Cach F, Villa-Tanaca ML, Trujillo-Ferrara JG, Aleman-Gonzalez-Duhart D, Quintana-Perez JC, Gonzalez-Ramirez IA, Correa-Basurto J (2016) In silico studies most employed in the discovery of new antimicrobial agents. Curr Med Chem

    Google Scholar 

  • Tanabe K, Lamping E, Adachi K, Takano Y, Kawabata K, Shizuri Y, Niimi M, Uehara Y (2007) Inhibition of fungal ABC transporters by unnarmicin A and unnarmicin C, novel cyclic peptides from marine bacterium. Biochem Biophys Res Commun 364(4):990–995. doi:10.1016/j.bbrc.2007.10.110

    Article  CAS  PubMed  Google Scholar 

  • Tanabe K, Lamping E, Nagi M, Okawada A, Holmes AR, Miyazaki Y, Cannon RD, Monk BC, Niimi M (2011) Chimeras of Candida albicans Cdr1p and Cdr2p reveal features of pleiotropic drug resistance transporter structure and function. Mol Microbiol 82(2):416–433. doi:10.1111/j.1365-2958.2011.07820.x

    Article  CAS  PubMed  Google Scholar 

  • Thakur JK, Arthanari H, Yang F, Pan SJ, Fan X, Breger J, Frueh DP, Gulshan K, Li DK, Mylonakis E, Struhl K, Moye-Rowley WS, Cormack BP, Wagner G, Naar AM (2008) A nuclear receptor-like pathway regulating multidrug resistance in fungi. Nature 452(7187):604–609. doi:10.1038/nature06836

    Article  CAS  PubMed  Google Scholar 

  • Thornewell SJ, Peery RB, Skatrud PL (1997) Cloning and characterization of CneMDR1: a Cryptococcus neoformans gene encoding a protein related to multidrug resistance proteins. Gene 201(1–2):21–29

    Article  CAS  PubMed  Google Scholar 

  • Tong AH, Boone C (2006) Synthetic genetic array analysis in Saccharomyces cerevisiae. Methods Mol Biol 313:171–192

    CAS  PubMed  Google Scholar 

  • Tsao S, Rahkhoodaee F, Raymond M (2009) Relative contributions of the Candida albicans ABC transporters Cdr1p and Cdr2p to clinical azole resistance. Antimicrob Agents Chemother 53(4):1344–1352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tusnady GE, Sarkadi B, Simon I, Varadi A (2006) Membrane topology of human ABC proteins. FEBS Lett 580(4):1017–1022

    Article  CAS  PubMed  Google Scholar 

  • van den Brule S, Smart CC (2002) The plant PDR family of ABC transporters. Planta 216(1):95–106

    Article  PubMed  CAS  Google Scholar 

  • Vandeputte P, Ferrari S, Coste AT (2012) Antifungal resistance and new strategies to control fungal infections. Int J Microbiol 2012:713687. doi:10.1155/2012/713687

    Article  PubMed  CAS  Google Scholar 

  • Venkatesh M, Wang H, Cayer J, Leroux M, Salvail D, Das B, Wrobel JE, Mani S (2011) In vivo and in vitro characterization of a first-in-class novel azole analog that targets pregnane X receptor activation. Mol Pharmacol 80(1):124–135. doi:10.1124/mol.111.071787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vermitsky JP, Edlind TD (2004) Azole resistance in Candida glabrata: coordinate upregulation of multidrug transporters and evidence for a Pdr1-like transcription factor. Antimicrob Agents Chemother 48(10):3773–3781. doi:10.1128/AAC.48.10.3773-3781.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vermitsky JP, Earhart KD, Smith WL, Homayouni R, Edlind TD, Rogers PD (2006) Pdr1 regulates multidrug resistance in Candida glabrata: gene disruption and genome-wide expression studies. Mol Microbiol 61(3):704–722

    Article  CAS  PubMed  Google Scholar 

  • Verrier PJ, Bird D, Burla B, Dassa E, Forestier C, Geisler M, Klein M, Kolukisaoglu U, Lee Y, Martinoia E, Murphy A, Rea PA, Samuels L, Schulz B, Spalding EJ, Yazaki K, Theodoulou FL (2008) Plant ABC proteins—a unified nomenclature and updated inventory. Trends Plant Sci 13(4):151–159

    Article  CAS  PubMed  Google Scholar 

  • Wada S, Niimi M, Niimi K, Holmes AR, Monk BC, Cannon RD, Uehara Y (2002) Candida glabrata ATP-binding cassette transporters Cdr1p and Pdh1p expressed in a Saccharomyces cerevisiae strain deficient in membrane transporters show phosphorylation-dependent pumping properties. J Biol Chem 277(48):46809–46821

    Article  CAS  PubMed  Google Scholar 

  • Wada S, Tanabe K, Yamazaki A, Niimi M, Uehara Y, Niimi K, Lamping E, Cannon RD, Monk BC (2005) Phosphorylation of Candida glabrata ATP-binding cassette transporter Cdr1p regulates drug efflux activity and ATPase stability. J Biol Chem 280(1):94–103

    Article  CAS  PubMed  Google Scholar 

  • White TC (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(7):1482–1487

    CAS  PubMed  PubMed Central  Google Scholar 

  • White TC, Marr KA, Bowden RA (1998) Clinical, cellular, and molecular factors that contribute to antifungal drug resistance. Clin Microbiol Rev 11(2):382–402

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wirsching S, Michel S, Kohler G, Morschhauser J (2000a) Activation of the multiple drug resistance gene MDR1 in fluconazole-resistant, clinical Candida albicans strains is caused by mutations in a trans-regulatory factor. J Bacteriol 182(2):400–404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wirsching S, Michel S, Morschhauser J (2000b) Targeted gene disruption in Candida albicans wild-type strains: the role of the MDR1 gene in fluconazole resistance of clinical Candida albicans isolates. Mol Microbiol 36(4):856–865

    Article  CAS  PubMed  Google Scholar 

  • Wolfe KH, Shields DC (1997) Molecular evidence for an ancient duplication of the entire yeast genome. Nature 387(6634):708–713

    Article  CAS  PubMed  Google Scholar 

  • Wortman JR, Fedorova N, Crabtree J, Joardar V, Maiti R, Haas BJ, Amedeo P, Lee E, Angiuoli SV, Jiang B, Anderson MJ, Denning DW, White OR, Nierman WC (2006) Whole genome comparison of the A. fumigatus family. Med Mycol 44(Suppl):3–7

    Article  CAS  Google Scholar 

  • Yamamoto S, Hiraga K, Abiko A, Hamanaka N, Oda K (2005) A new function of isonitrile as an inhibitor of the Pdr5p multidrug ABC transporter in Saccharomyces cerevisiae. Biochem Biophys Res Commun 330(2):622–628. doi:10.1016/j.bbrc.2005.03.009

    Article  CAS  PubMed  Google Scholar 

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    Brian C. Monk & Mikhail V. Keniya

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    Rajendra Prasad

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Monk, B.C., Keniya, M.V. (2017). Using Yeast to Discover Inhibitors of Multidrug Efflux in Candida albicans . In: Prasad, R. (eds) Candida albicans: Cellular and Molecular Biology. Springer, Cham. https://doi.org/10.1007/978-3-319-50409-4_23

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