Candida Efflux ATPases and Antiporters in Clinical Drug Resistance

  • Rajendra PrasadEmail author
  • Manpreet Kaur Rawal
  • Abdul Haseeb Shah
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 892)


An enhanced expression of genes encoding ATP binding cassette (ABC) and major facilitator superfamily (MFS) transport proteins are known to contribute to the development of tolerance to antifungals in pathogenic yeasts. For example, the azole resistant (AR) clinical isolates of the opportunistic human fungal pathogen Candida albicans show an overexpression of CDR1 and/or CaMDR1 belonging to ABC and MFS, superfamilies, respectively. The reduced accumulation (due to rapid efflux) of drugs in AR isolates confirms the role of efflux pump proteins in the development of drug tolerance. Considering the importance of major multidrug transporters, the focus of recent research has been to understand the structure and function of these proteins which could help to design inhibitors/modulators of these pump proteins. This chapter focuses on some aspects of the structure and function of yeast transporter proteins particularly in relation to MDR in Candida.


Drug resistance ABC transporters MFS transporters Cdr1p CaMdr1p 


  1. 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 323:1718–1722PubMedPubMedCentralCrossRefGoogle Scholar
  2. Ananthaswamy N, Rutledge R, Sauna ZE, Ambudkar SV, Dine E, Nelson E, Xia D, Gollin J (2010) The signaling interface of the yeast multidrug transporter Pdr5 adopts a cis conformation, and there are functional overlap and equivalence of the deviant and canonical Q-loop residues. Biochemistry 49:4440–4449PubMedPubMedCentralCrossRefGoogle Scholar
  3. Balzi E, Wang M, Leterme S, Van Dyck L, Goffeau A (1994) PDR5, a novel yeast multidrug resistance conferring transporter controlled by the transcription regulator PDR1. J Biol Chem 269:2206–2214PubMedGoogle Scholar
  4. Barker KS, Pearson MM, Rogers PD (2003) Identification of genes differentially expressed in association with reduced azole susceptibility in Saccharomyces cerevisiae. J Antimicrob Chemother 51:1131–1140PubMedCrossRefGoogle Scholar
  5. Ben-Yaacov R, Knoller S, Caldwell GA, Becker JM, Koltin Y (1994) Candida albicans gene encoding resistance to benomyl and methotrexate is a multidrug resistance gene. Antimicrob Agents Chemother 38:648–652PubMedPubMedCentralCrossRefGoogle Scholar
  6. Braun BR, Vanhet HM, d’Enfert C, Martchenko M, Dungan J, Kuo A, Inglis DO et al (2005) A human-curated annotation of the Candida albicans genome. PLoS Genet 1:36–57PubMedCrossRefGoogle Scholar
  7. Cabrito TR, Teixeira MC, Singh A, Prasad R, Sa-Correia I (2011) The yeast ABC transporter Pdr18 (ORF YNR070w) controls plasma membrane sterol composition, playing a role in multidrug resistance. Biochem J 440:195–202PubMedPubMedCentralCrossRefGoogle Scholar
  8. Calabrese D, Bille J, Sanglard D (2000) A novel multidrug efflux transporter gene of the major facilitator superfamily from Candida albicans (FLU1) conferring resistance to fluconazole. Microbiology 146:2743–2754PubMedCrossRefGoogle Scholar
  9. 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 22:291–321PubMedPubMedCentralCrossRefGoogle Scholar
  10. Christensen PU, Davis K, Nielsen O, Davey J (1997a) Abc1: a new ABC transporter from the fission yeast Schizosaccharomyces pombe. FEMS Microbiol Lett 147:97–102PubMedCrossRefGoogle Scholar
  11. Christensen PU, Davey J, Nielsen O (1997b) The Schizosaccharomyces pombe mam1 gene encodes an ABC transporter mediating secretion of M-factor. Mol Gen Genet 255:226–236PubMedCrossRefGoogle Scholar
  12. Costa C, Pires C, Cabrito TR, Renaudin A, Ohno M, Chibana H, Sa-Correia I, Teixeira MC (2013) Candida glabrata drug: H+ antiporter CgQdr2 confers imidazole drug resistance, being activated by transcription factor CgPdr1. Antimicrob Agents Chemother 57:3159–3167. doi: 10.1128/AAC.00811-12 PubMedPubMedCentralCrossRefGoogle Scholar
  13. Dassa E, Bouige P (2001) The ABC of ABCS: a phylogenetic and functional classification of ABC systems in living organisms. Res Microbiol 152:211–229PubMedCrossRefGoogle Scholar
  14. Dawson RJ, Locher KP (2006) Structure of a bacterial multidrug ABC transporter. Nature 443:180–185PubMedCrossRefGoogle Scholar
  15. Dean M, Allikmets R, Gerrard B, Stewart C, Kistler A, Shafer B, Michaelis S, Strathern J (1994) Mapping and sequencing of two yeast genes belonging to the ATP- binding cassete superfamily. Yeast 10:377–383PubMedCrossRefGoogle Scholar
  16. Dean M, Andrey R, Rando A (2001) The human ATP-binding cassette (ABC) transporter superfamily. Genome Res 11:1156–1166PubMedCrossRefGoogle Scholar
  17. Decottignies A, Goffeau A (1997) Complete inventory of the yeast ABC proteins. Nat Genet 15:137–145PubMedCrossRefGoogle Scholar
  18. 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 270:18150–18157PubMedCrossRefGoogle Scholar
  19. 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 273:12612–12622PubMedCrossRefGoogle Scholar
  20. Dejos C, Régnacq M, Bernard M, Voisin P, Bergès T (2013) The MFS-type efflux pump Flr1 induced by Yap1 promotes canthin-6-one resistance in yeast. FEBS Lett 587:3045–3051PubMedCrossRefGoogle Scholar
  21. Dogra S, Krishnamurthy S, Gupta V, Dixit BL, Gupta CM, Sanglard D, Prasad R (1999) Asymmetric distribution of phosphatidylethanolamine in C. albicans: possible mediation by CDR1, a multidrug transporter belonging to ATP binding cassette (ABC) superfamily. Yeast 15:111–121PubMedCrossRefGoogle Scholar
  22. Felder T, Bogengruber E, Tenreiro S, Ellinger A, Sá-Correia I, Briza P (2002) Dtrlp, a multidrug resistance transporter of the major facilitator superfamily, plays an essential role in spore wall maturation in Saccharomyces cerevisiae. Eukaryot Cell 1:799–810PubMedPubMedCentralCrossRefGoogle Scholar
  23. Franz R, Michel S, Morschhauser J (1998) A fourth gene from the Candida albicans CDR family of ABC transporters. Gene 220:91–98PubMedCrossRefGoogle Scholar
  24. Fritz F, Howard EM, Hoffman MM, Roepe P (1999) Evidence for altered ion transport in Saccharomyces cerevisiae overexpressing human MDR 1 protein. Biochemistry 38:4214–4226PubMedCrossRefGoogle Scholar
  25. Gaur M, Choudhury D, Prasad R (2005) Complete inventory of ABC proteins in human pathogenic yeast, Candida albicans. J Mol Microbiol Biotechnol 9:3–15PubMedCrossRefGoogle Scholar
  26. Gaur M, Puri N, Manoharlal R, Rai V, Mukhopadhayay G, Choudhary D, Prasad R (2008) MFS transportome of the human pathogenic yeast Candida albicans. BMC Genomics 9:579. doi: 10.1186/1471-2164-9-579 PubMedPubMedCentralCrossRefGoogle Scholar
  27. Ginn SL, Brown MH, Skurray RA (2000) The TetA(K) tetracycline/H(+) antiporter from Staphylococcus aureus: mutagenesis and functional analysis of motif C. J Bacteriol 182:1492–1498. doi: 10.1128/JB.182.6.1492-1498.2000 PubMedPubMedCentralCrossRefGoogle Scholar
  28. Goldman BS, Kranz RG (2001) ABC transporters associated with cytochrome c biogenesis. Res Microbiol 152:323–329PubMedCrossRefGoogle Scholar
  29. Gupta V, Kohli AK, Krishnamurthy S, Puri N, Aalamgeer SA, Panwar SL, Prasad R (1998) Identification of mutant alleles of CaMDR1, a major facilitator of Candida albicans which confers multidrug resistance and its in vitro transcriptional activation. Curr Genet 3:192–199CrossRefGoogle Scholar
  30. Higgins CF, Linton KJ (2004) The ATP switch model for ABC transporters. Nat Struct Mol Biol 11:918–926PubMedCrossRefGoogle Scholar
  31. 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 328:1119–1125PubMedCrossRefGoogle Scholar
  32. Huang J, Zhang Y, Peng JS, Zhong C, Yi HY, Ow DW, Gong JM (2012) Fission yeast HMT1 lowers seed cadmium through phytochelatin-dependent vacuolar sequestration in Arabidopsis. Plant Physiol 158:1779–1788. doi: 10.1104/pp.111.192872 PubMedPubMedCentralCrossRefGoogle Scholar
  33. Iwaki T, Fujita Y, Tanaka N, Giga-Hama Y, Takegawa K (2005) Mitochondrial ABC transporter Atm1p is required for protection against oxidative stress and vacuolar functions in Schizosaccharomyces pombe. Biosci Biotechnol Biochem 69:2109–2116PubMedCrossRefGoogle Scholar
  34. Iwaki T, Giga-Hama Y, Takegawa K (2006) A survey of all 11 ABC transporters in fission yeast: two novel ABC transporters are required for red pigment accumulation in a Schizosaccharomyces pombe adenine biosynthetic mutant. Microbiology 152:2309–2321PubMedCrossRefGoogle Scholar
  35. Jacquot C, Julien R, Guilloton M (1997) The Saccharomyces cerevisiae MFS superfamily SGE1 gene confers resistance to cationic dyes. Yeast 13:891–902PubMedCrossRefGoogle Scholar
  36. Jha S, Karnani N, Dhar SK, Mukhopadhayay K, Shukla S, Saini P, Mukhopadhayay G, Prasad R (2003) Purification and characterization of the N-terminal nucleotide binding domain of an ABC drug transporter of Candida albicans: uncommon cysteine 193 of Walker A is critical for ATP hydrolysis. Biochemistry 42:10822–10832PubMedCrossRefGoogle Scholar
  37. Jha S, Dabas N, Karnani N, Saini P, Prasad R (2004) ABC multidrug transporter Cdr1p of Candida albicans has divergent nucleotide-binding domains which display functional asymmetry. FEMS Yeast Res 5:63–72PubMedCrossRefGoogle Scholar
  38. Kapoor K, Rehan M, Kaushiki A, Pasrija R, Lynn AM, Prasad R (2009) Rational mutational analysis of a multidrug MFS transporter CaMdr1p of Candida albicans by employing a membrane environment based computational approach. PLoS Comput Biol 5:1–11CrossRefGoogle Scholar
  39. Kapoor K, Rehan M, Lynn AM, Prasad R (2010) Employing information theoretic measures and mutagenesis to identify residues critical for drug-proton antiport function in Mdr1p of Candida albicans. PLoS One 5(6):e11041. doi: 10.1371/journal.pone.0011041 PubMedPubMedCentralCrossRefGoogle Scholar
  40. Katiyar SK, Edlind TD (2001) Identification and expression of multidrug resistance-related ABC transporter gene in Candida krusei. Med Mycol 39:109–116PubMedCrossRefGoogle Scholar
  41. Katzmann DJ, Hallstrom TC, Voet M, Wysock W, Golin J, Volckert G, Moye-Rowley WS (1995) Expression of an ATP-binding cassette transporter-encoding gene (YOR1) is required for oligomycin resistance in Saccharomyces cerevisiae. Mol Cell Biol 15:6875–6883PubMedPubMedCentralCrossRefGoogle Scholar
  42. Kaya A, Karakaya HC, Fomenko DE, Gladyshev VN, Koc A (2009) Identification of a novel system for boron transport: Atr1 is a main boron exporter in yeast. Mol Cell Biol 29:3665–3674PubMedPubMedCentralCrossRefGoogle Scholar
  43. Kispal G, Csere P, Guiard B, Lill R (1997) The ABC transporter Atm1p is required for mitochondrial iron homeostasis. FEBS Lett 418:346–350PubMedCrossRefGoogle Scholar
  44. Krishnamurthy S, Gupta V, Prasad R, Panwar SL, Prasad R (1998) Expression of CDR1, a multidrug resistance gene of Candida albicans: In vitro transcriptional activation by heat shock, drugs and human steroid hormones. FEMS Microbiol Lett 160:191–197PubMedCrossRefGoogle Scholar
  45. Lamping E, Baret PV, Holmes AR, Monk BC, Goffeau A, Cannon RD (2010) Fungal PDR transporters: phylogeny, topology, motifs and function. Fungal Genet Biol 47:117–142CrossRefGoogle Scholar
  46. Lee MD, Galazzo JL, Staley AL, Lee JC, Warren W, Fuernkranz H, Chamberland S, Lomovskaya O, Miller GH (2001) Microbial fermentation-derived inhibitors of efflux-pump-mediated drug resistance. Farmaco 56:81–85PubMedCrossRefGoogle Scholar
  47. Leighton J, Schatz G (1995) An ABC transporter in the mitochondrial inner membrane is required for normal growth of yeast. EMBO J 14:188–195PubMedPubMedCentralGoogle Scholar
  48. Li ZS, Szczypka M, Lu YP, Thiele DJ, Rea PA (1996) The yeast cadmium factor protein (YCF1) is a vacuolar glutathione S-conjugate pump. J Biol Chem 271:6509–6517PubMedCrossRefGoogle Scholar
  49. Liu HY, Chiang YC, Pan J, Chen J, Salvadore C, Audino DC, Badarinarayana V, Palaniswamy V, Anderson B, Denis CL (2001) Characterization of CAF4 and CAF16 reveals a functional connection between the CCR4-NOT complex and a subset of SRB proteins of the RNA polymerase II holoenzyme. J Biol Chem 276:7541–7548PubMedCrossRefGoogle Scholar
  50. Mandal A, Kumar A, Singh A, Lynn AM, Kapoor K, Prasad R (2012) A key structural domain of the Candida albicans Mdr1 protein. Biochem J 445:313–322PubMedCrossRefGoogle Scholar
  51. McGrath JP, Vershavsky A (1989) The yeast STE6 gene encodes a homologue of the mammalian multidrug resistance P-glycoprotein. Nature 340:400–404PubMedCrossRefGoogle Scholar
  52. Mendez C, Salas JA (2001) The role of ABC transporters in antibiotic producing organisms: drug secretion and resistance mechanisms. Res Microbiol 152:341–350PubMedCrossRefGoogle Scholar
  53. Mendoza-Cózatl DG, Zhai Z, Jobe TO, Akmakjian GZ, Song WY et al (2010) Tonoplast-localized Abc2 transporter mediates phytochelatin accumulation in vacuoles and confers cadmium tolerance. J Biol Chem 285:40416–40426PubMedPubMedCentralCrossRefGoogle Scholar
  54. Miyazaki H, Miyazaki Y, Geber A, Parkinson T, Hitchcock CA, 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 42:1695–1701PubMedPubMedCentralGoogle Scholar
  55. Moran GP, Sanglard D, Donnelly SM, Shanley DB, Sullivan DJ, Coleman DC (1998) Identification and expression of multidrug transporters responsible for fluconazole resistance in Candida dubliniensis. Antimicrob Agents Chemother 42:1819–1830PubMedPubMedCentralGoogle Scholar
  56. Nagao K, Taguchi Y, Arioka M, Kadokura H, Takatsuki A, Yoda K, Yamasaki M (1995) bfr1+, a novel gene of Schizosaccharomyces pombe which confers brefeldin A resistance, is structurally related to the ATP-binding cassette superfamily. J Bacteriol 177:1536–1543PubMedPubMedCentralCrossRefGoogle Scholar
  57. 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 45:3366–3374PubMedPubMedCentralCrossRefGoogle Scholar
  58. Nakayama H, Tanabe K, Bard M, Hodgson W, Wu S, Takemori D, Aoyama T, Kumaraswami NS, Metzler L, Takano Y, Chibana H, Niimi M (2007) The Candida glabrata putative sterol transporter gene CgAUS1 protects cells against azoles in the presence of serum. J Antimicrob Chemother 60:1264–1272PubMedCrossRefGoogle Scholar
  59. 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 48:1256–1271PubMedPubMedCentralCrossRefGoogle Scholar
  60. 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 14:624–632. doi: 10.1111/1567-1364 12149 PubMedCrossRefGoogle Scholar
  61. Nishi K, Yoshida M, Horinouchi S, Beppu T (1993) Mating of the fission yeast independently of pmd1+ gene product, a structural homologue of budding yeast STE6 and mammalian P-glycoproteins. Arch Microbiol 160:162–165PubMedCrossRefGoogle Scholar
  62. Nunes PA, Tenreiro S, Sá-Correia I (2001) Resistance and adaptation to quinidine in Saccharomyces cerevisiae: role of QDR1 (YIL120w), encoding a plasma membrane transporter of the major facilitator superfamily required for multidrug resistance. Antimicrob Agents Chemother 45:1528–1534PubMedPubMedCentralCrossRefGoogle Scholar
  63. Ogawa A, Hashida Okado T, Endo M, Yoshioka H, Tsuruo T, Takesako K, Kato I (1998) Role of ABC transporters in aureobasidin A resistance. Antimicrob Agents Chemother 42:755–761PubMedPubMedCentralCrossRefGoogle Scholar
  64. Ortiz DF, Pierre MV, Abdulmessih A, Arias IM (1997) A yeast ATP binding cassette-type protein mediating ATP-dependent bile acid transport. J Biol Chem 272:15358–15365PubMedCrossRefGoogle Scholar
  65. Pagant S, Halliday JJ, Kougentakis C, Miller EA (2010) Intragenic suppressing mutations correct the folding and intracellular traffic of misfolded mutants of Yor1p, a eukaryotic drug transporter. J Biol Chem 285:36304–36314PubMedPubMedCentralCrossRefGoogle Scholar
  66. Pao SS, Paulsen IT, Saier MH Jr (1998) Major facilitator superfamily. Microbiol Mol Biol Rev 62:1–34PubMedPubMedCentralGoogle Scholar
  67. Pasrija R, Banerjee D, Prasad R (2007) Structure and function analysis of CaMdr1p, a MFS antifungal efflux transporter protein of Candida albicans: identification of amino acid residues critical for drug/H+ transport. Eukaryot Cell 6:443–453PubMedPubMedCentralCrossRefGoogle Scholar
  68. 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 124:1–11PubMedCrossRefGoogle Scholar
  69. Paulsen IT, Brown MH, Skurray RA (1996) Proton-dependent multidrug efflux systems. Microbiol Rev 60:575–608PubMedPubMedCentralGoogle Scholar
  70. Perlin DS (2011) Current perspectives on echinocandin class drugs. Future Microbiol 6:41–57CrossRefGoogle Scholar
  71. Pfaller MA, Diekema DJ (2007) Epidemiology of invasive candidiasis: a persistent public health problem. Clin Microbiol Rev 20:133–163PubMedPubMedCentralCrossRefGoogle Scholar
  72. Pfaller MA, Andes DR, Diekema DJ, Horn DL, Reboli AC, Rotstein C, Franks B, Azie NE (2014) Epidemiology and outcomes of invasive candidiasis due to non-albicans species of Candida in 2,496 patients: data from the Prospective Antifungal Therapy (PATH) registry 2004–2008. PLoS One 9(7):e101510. doi: 10.1371/journal.pone.0101510. eCollection 2014PubMedPubMedCentralCrossRefGoogle Scholar
  73. Pina-Vaz C, Rodrigues AG, Costa-de-Oliveira S, Ricardo E, Mardh PA (2005) Potent synergic effect between ibuprofen and azoles on Candida resulting from blockade of efflux pumps as determined by FUN-1 staining and flow cytometry. J Antimicrob Chemother 56:678–685PubMedCrossRefGoogle Scholar
  74. Piper P, Mahe Y, Thompson S, Pandjaitan R, Holyoak C, Egner R, Muhlbauer M, Coote P, Kuchler K (1998) The Pdr12 ABC transporter is required for the development of weak organic acid resistance in yeast. EMBO J 17:4257–4265PubMedPubMedCentralCrossRefGoogle Scholar
  75. Prasad R, Goffeau A (2012) Yeast ATP binding cassette transporters conferring multidrug resistance. Annu Rev Microbiol 66:39–63PubMedCrossRefGoogle Scholar
  76. Prasad R, Rawal MK (2014) Efflux pump proteins in antifungal resistance. Front Pharmacol 5:202. doi: 10.3389/fphar.2014.00202. eCollection 2014. ReviewPubMedPubMedCentralCrossRefGoogle Scholar
  77. Prasad R, Worgifosse PD, Goffeau A, Balzi E (1995) Molecular cloning and characterisation of a novel gene of C. albicans, CDR1, conferring multiple resistance to drugs and antifungals. Curr Genet 27:320–329PubMedCrossRefGoogle Scholar
  78. Prasad R, Panwar SL, Smriti (2002) Drug resistance in yeasts as an emerging scenario. Adv Microb Physiol 46:155–201PubMedCrossRefGoogle Scholar
  79. Puri N, Gaur M, Sharma M, Shukla S, Ambudkar SV, Prasad R (2009) The amino acid residues of transmembrane helix 5 of multidrug resistance protein CaCdr1p of Candida albicans are involved in substrate specificity and drug transport. Biochim Biophys Acta 1788:1752–1761PubMedPubMedCentralCrossRefGoogle Scholar
  80. Puri N, Prakash O, Manoharlal R, Sharma M, Ghosh I, Prasad R (2010) Analysis of physico-chemical properties of substrates of ABC and MFS multidrug transporters of pathogenic Candida albicans. Eur J Med Chem 45:4813–4826PubMedCrossRefGoogle Scholar
  81. Purnelle B, Skala J, Goffeau A (1991) The product of the YCR105 gene located on the chromosome III from Saccharomyces cerevisiae presents homologies to ATP-dependent permeases. Yeast 7:867–872PubMedCrossRefGoogle Scholar
  82. Rai V, Shukla S, Jha S, Komath SS, Prasad R (2005) Functional characterization of N-terminal nucleotide binding domain (NBD-1) of a major ABC drug transporter Cdr1p of Candida albicans: uncommon but conserved Trp326 of Walker B is important for ATP binding. Biochemistry 44:6650–6661PubMedCrossRefGoogle Scholar
  83. Rai V, Gaur M, Shukla S, Shukla S, Ambudkar SV, Komath SS, Prasad R (2006) Conserved Asp327 of Walker B motif in the N-terminal nucleotide binding domain (NBD-1) of Cdr1p of Candida albicans has acquired a new role in ATP hydrolysis. Biochemistry 45:14726–14739PubMedPubMedCentralCrossRefGoogle Scholar
  84. Rawal MK, Khan MF, Kapoor K, Goyal N, Sen S, Saxena AK, Lynn AM, Tyndal 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 288:24480–24493. doi: 10.1074/jbc.M113.488353 PubMedPubMedCentralCrossRefGoogle Scholar
  85. Raymond M, Dignard D, Alarco AM, Mainville N, Magee BB, Thomas DY (1998) A Ste6p/P-glycoprotein homologue from the asexual yeast Candida albicans transports the a-factor mating pheromone in Saccharomyces cerevisiae. Mol Microbiol 27:587–598PubMedCrossRefGoogle Scholar
  86. Reboutier D, Piednoel M, Boisnard S, Conti A, Chevalier V, Florent M, Gibot-Leclerc S, Da Silva B, Chastin C, Fallague K, Favel A, Noël T, Ruprich-Robert G, Chapeland-Leclerc F, Papon N (2009) Combination of different molecular mechanisms leading to fluconazole resistance in a Candida lusitaniae clinical isolate. Diagn Microbiol Infect Dis 63:188–193. doi: 10.1016/j.diagmicrobio.2008.10.019 PubMedCrossRefGoogle Scholar
  87. Richardson DM (2005) Changing patterns and trends in systemic function infections. J Antimicrob Chemother 56:5–112CrossRefGoogle Scholar
  88. Saier MH Jr, Reizer J (1991) Families and super families of transport proteins common to prokaryotes and eukaryotes. Curr Opinion Struct Biol 1:362–368CrossRefGoogle Scholar
  89. Saini P, Prasad T, Gaur NA, Shukla S, Jha S, Komath SS, Khan LA, Haq QMR, 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 56:77–86PubMedCrossRefGoogle Scholar
  90. Saini P, Gaur NA, Prasad R (2006) Chimeras of the ABC drug transporter Cdr1p reveal functional indispensability of transmembrane domains and nucleotide-binding domains, but transmembrane segment 12 is replaceable with the corresponding homologous region of the non-drug transporter Cdr3p. Microbiology 152:1559–1573PubMedCrossRefGoogle Scholar
  91. Sandbaken MG, Lupisella JA, DiDomenico B, Chakraburtty K (1990) Protein synthesis in yeast. Structural and functional analysis of the gene encoding elongation factor 3. J Biol Chem 265:15838–15844PubMedGoogle Scholar
  92. 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 39:2378–2386PubMedPubMedCentralCrossRefGoogle Scholar
  93. Sanglard D, Ischer F, Monod M, Bille J (1997) Cloning of Candida albicans genes conferring resistance to azole antifungal agents: characterisation of CDR2, a new multidrug ABC transporter gene. Microbiology 143:405–416PubMedCrossRefGoogle Scholar
  94. 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 43:2753–2765PubMedPubMedCentralGoogle Scholar
  95. 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 74:1352–1359PubMedPubMedCentralCrossRefGoogle Scholar
  96. Sasnauskas K, Jomantiene R, Lebediene E, Lebedys J, Januska A, Janulaitis A (1992) Cloning and sequence analysis of a Candida maltosa gene which confers resistance to cycloheximide. Gene 116:105–108PubMedCrossRefGoogle Scholar
  97. Sasser TL, Padolina M, Fratti RA (2012) The yeast vacuolar ABC transporter Ybt1p regulates membrane fusion through Ca2+ transport modulation. Biochem J 448:365–372. doi: 10.1042/BJ20120847 PubMedPubMedCentralCrossRefGoogle Scholar
  98. 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 283:35010–35022PubMedPubMedCentralCrossRefGoogle Scholar
  99. Schneider E (2001) ABC transporters catalyzing carbohydrate uptake. Res Microbiol 152:303–310PubMedCrossRefGoogle Scholar
  100. Schneider E, Hunke S (1998) ATP-binding-cassette (ABC) transport systems: functional and structural aspects of the ATP-hydrolyzing subunits/domains. FEMS Microbiol Rev 22:1–20PubMedCrossRefGoogle Scholar
  101. Schuetzer-Muehlbauer M, Willinger B, Egner R, Ecker G, Kuchler K (2003) Reversal of antifungal resistance mediated by ABC efflux pumps from Candida albicans functionally expressed in yeast. Int J Antimicrob Agents 22:291–300PubMedCrossRefGoogle Scholar
  102. Shani N, Valle D (1996) A Saccharomyces cerevisiae homolog of the human adrenoleukodystrophy transporter is a heterodimer of two half ATP-binding cassette transporters. Proc Natl Acad Sci U S A 93:11901–11906PubMedPubMedCentralCrossRefGoogle Scholar
  103. Shani N, Watkins PA, Valle D (1995) PXA1, a possible Saccharomyces cerevisiae ortholog of the human adrenoleukodystrophy gene. Proc Natl Acad Sci U S A 92:6012–6016PubMedPubMedCentralCrossRefGoogle Scholar
  104. 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 55:4834–4843PubMedPubMedCentralCrossRefGoogle Scholar
  105. 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 53:3256–3265PubMedPubMedCentralCrossRefGoogle Scholar
  106. Shimazu M, Sekito T, Akiyama K, Ohsumi Y, Kakinuma Y (2005) A family of basic amino acid transporters of the vacuolar membrane from Saccharomyces cerevisiae. J Biol Chem 280:4851–4857PubMedCrossRefGoogle Scholar
  107. Shukla S, Saini P, Smriti JS, Ambudkar SV, Prasad R (2003) Functional characterization of Candida albicans ABC transporter Cdr1p. Eukaryot Cell 2:1361–1375PubMedPubMedCentralCrossRefGoogle Scholar
  108. 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 322:520–525PubMedCrossRefGoogle Scholar
  109. Smith WL, Edlind TD (2002) Histone deacetylase inhibitors enhance Candida albicans sensitivity to azoles and related antifungals: correlation with reduction in CDR and ERG upregulation. Antimicrob Agents Chemother 46:3532–3539PubMedPubMedCentralCrossRefGoogle Scholar
  110. Smriti Krishnamurthy S, 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 19:303–318PubMedCrossRefGoogle Scholar
  111. Stolz J, Wöhrmann HJ, Vogl C (2005) Amiloride uptake and toxicity in fission yeast are caused by the pyridoxine transporter encoded by bsu1+ (car1+). Eukaryot Cell 4:319–326PubMedPubMedCentralCrossRefGoogle Scholar
  112. Sturtevant J, Cihlar R, Calderone R (1998) Disruption studies of a Candida albicans gene, ELF1: a member of the ATP-binding cassette family. Microbiology 144:2311–2321PubMedCrossRefGoogle Scholar
  113. 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 364:990–995PubMedCrossRefGoogle Scholar
  114. Tenreiro S, Rosa PC, Viegas CA, Sa-Correia I (2000) Expression of the AZR1 gene (ORF YGR224w), encoding a plasma membrane transporter of the major facilitator superfamily, is required for adaptation to acetic acid and resistance to azoles in Saccharomyces cerevisiae. Yeast 16:1469–1481PubMedCrossRefGoogle Scholar
  115. Tenreiro S, Nunes PA, Viegas CA, Neves MS, Teixeira MC, Cabral MG, Sa-Correia I (2002) AQR1 gene (ORF YNL065w) encodes a plasma membrane transporter of the major facilitator superfamily that confers resistance to short-chain monocarboxylic acids and quinidine in Saccharomyces cerevisiae. Biochem Biophys Res Commun 292:741–748PubMedCrossRefGoogle Scholar
  116. Tenreiro S, Vargas RC, Teixeira MC, Magnani C, Sa-Correia I (2005) The yeast multidrug transporter Qdr3 (Ybr043c): localization and role as a determinant of resistance to quinidine, barban, cisplatin, and bleomycin. Biochem Biophys Res Commun 327:952–959PubMedCrossRefGoogle Scholar
  117. Theiss S, Kretschmar M, Nichterlein T, Hof H, Agabian N, Hacker J, Kohler GA (2002) Functional analysis of a vacuolar ABC transporter in wild-type Candida albicans reveals its involvement in virulence. Mol Microbiol 43:571–584PubMedCrossRefGoogle Scholar
  118. 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 201:21–29PubMedCrossRefGoogle Scholar
  119. Tomitori H, Kashiwagi K, Asakawa T, Kakinuma Y, Michael AJ, Igarashi K (2001) Multiple polyamine transport systems on the vacuolar membrane in yeast. Biochem J 353:681–688PubMedPubMedCentralCrossRefGoogle Scholar
  120. Torelli R, Posteraro B, Ferrari S, La Sorda M, Fadda G, Sanglard D, Sanguinetti M (2008) The ATP-binding cassette transporter-encoding gene CgSNQ2 is contributing to the CgPDR1-dependent azole resistance of Candida glabrata. Mol Microbiol 68:186–201. doi: 10.1111/j.1365-2958.2008.06143.x PubMedCrossRefGoogle Scholar
  121. Vargas RC, Garcia-Salcedo R, Tenreiro S, Teixeira MC, Fernandes AR, Ramos J, Sa-Correia I (2007) Saccharomyces cerevisiae multidrug resistance transporter Qdr2 is implicated in potassium uptake, providing a physiological advantage to quinidine-stressed cells. Eukaryot Cell 6:134–142PubMedCrossRefGoogle Scholar
  122. Vazquez de Aldana CR, Marton MJ, Hinnebusch AG (1995) GCN20, a novel ATP binding cassette protein, and GCN1 reside in a complex that mediates activation of the eIF-2 alpha kinase GCN2 in amino acid-starved cells. EMBO J 14:3184–3199PubMedPubMedCentralGoogle Scholar
  123. Wang Y, Cao YY, Jia XM, Cao YB, Gao PH, Fu XP, Ying K, Chen WS, Jiang YY (2006) Cap1p is involved in multiple pathways of oxidative stress response in Candida albicans. Free Radic Biol Med 40:1201–1209PubMedCrossRefGoogle Scholar
  124. Watkins WJ, Chong L, Cho A, Hilgenkamp R, Ludwikow M, Garizi N, Iqbal N, Barnard J, Singh R, Madsen D, Lolans K, Lomovskaya O, Oza U, Kumaraswamy P, Blecken A, Bai S, Loury DJ, Griffith DC, Dudley MN (2007) Quinazolinone fungal efflux pump inhibitors. Part 3: (N-Methyl)piperazine variants and pharmacokinetic optimization. Bioorg Med Chem Lett 17:2802–2806PubMedCrossRefGoogle Scholar
  125. Wawrzycka D, Sobczak I, Bartosz G, Bocer T, Ułaszewski S, Goffeau A (2010) Vmr 1p is a novel vacuolar multidrug resistance ABC transporter in Saccharomyces cerevisiae. FEMS Yeast Res 10:828–838. doi: 10.1111/j.1567-1364.2010.00673.x PubMedCrossRefGoogle Scholar
  126. Wilcox LJ, Balderes DA, Wharton B, Tinkelenberg AH, Rao G, Sturley SL (2002) Transcriptional profiling identifies two members of the ATP-binding cassette transporter superfamily required for sterol uptake in yeast. J Biol Chem 277:32466–32472PubMedCrossRefGoogle Scholar
  127. Wolfger H, Mahe Y, Parle-McDermott A, Delahodde A, Kuchler K (1997) The yeast ATP binding cassette (ABC) protein genes PDR10 and PDR15 are novel targets for the Pdr1 and Pdr3 transcriptional regulators. FEBS Lett 418:269–274PubMedCrossRefGoogle Scholar
  128. Wright MB, Howell EA, Gaber RF (1996) Amino acid substitutions in membrane-spanning domains of Hol1, a member of the major facilitator superfamily of transporters, confer nonselective cation uptake in Saccharomyces cerevisiae. J Bacteriol 178:7197–7205PubMedPubMedCentralCrossRefGoogle Scholar
  129. Wu CP, Ohnuma S, Ambudkar SV (2011) Discovering natural product modulators to overcome multidrug resistance in cancer chemotherapy. Curr Pharm Biotechnol 12:609–620PubMedPubMedCentralCrossRefGoogle Scholar
  130. 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 330:622–628PubMedCrossRefGoogle Scholar
  131. Yang Z, Huang J, Geng J, Nair U, Klionsky DJ (2006) Atg22 recycles amino acids to link the degradative and recycling functions of autophagy. Mol Biol Cell 17:5094–5104PubMedPubMedCentralCrossRefGoogle Scholar
  132. Yong VC, Chew LM, Kwan CL, Ng KP, Seow HF et al (2006) Transcriptional and sequencing analysis of CtCDR1, CtMDR1 and CtERG11 genes in fluconazole-resistant Candida tropicalis isolates from Candidemia patients. J Med Sci 6:713–723CrossRefGoogle Scholar
  133. Young L, Leonhard K, Tatsuta T, Trowsdale J, Langer T (2001) Role of the ABC transporter Mdl1 in peptide export from mitochondria. Science 291:2135–2138PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Rajendra Prasad
    • 1
    • 2
    Email author
  • Manpreet Kaur Rawal
    • 1
  • Abdul Haseeb Shah
    • 1
  1. 1.Membrane Biology Laboratory, School of Life SciencesJawaharlal Nehru UniversityNew DelhiIndia
  2. 2.AMITY Institute of Integrative Sciences and Health (AIISH)Amity University HaryanaManesar, GurgaonIndia

Personalised recommendations