Progress on the transcription factors associated with azole resistance in Candida albicans

Abstract

Abstract: Lately, the rate of Candida albicans infection kept increasing, more and more resistant strains had been detected with the wide use of azoles. Sogreat challenge had been brought to clinical treatment. Some molecular mechanisms associated with azole resistance had been described, including the point mutation ,overexpression of target enzyme, increased expression of efflux pump and the formation of biofilm. Since the transcription factors could regulate the expression of drug resistance genes, more and more attention has been paid to the contribution of zinc cluster transcription factors to drug resistance, such as TAC1, MRR1, MRR2, UPC2, NDT80, and so on. Lots of researches revealed that the point mutations of transcription factors could cause overexpression of their regulated resistance genes and finally led to drug resistance. The review focused on the research progress of the transcription factors.

Key words: Candida albicans, drug resistance mechanisms, TAC1, MRR1, UPC2, NDT80

CLC Number:

R379.4

WANG Ying, LIU Jin-yan, SHI Ce, XIANG Ming-jie. Progress on the transcription factors associated with azole resistance in Candida albicans[J]. Chinese Journal of Mycology, 2014, 9(4): 241-244,240.

References

[1] Chau AS, Mendrick CA, Sabatelli FJ, et al. Application of real-time quantitative PCR to molecular analysis of Candida albicans strains exhibiting reduced susceptibility to azoles[J].Antimicrob Agents Chemother,2004,48(6):2124-2131.
[2] Eddouzi J, Parker JE, Vale-Silva LA, et al. Molecular Mechanisms of Drug Resistance in Clinical Candida Species Isolated from Tunisian Hospitals[J].Antimicrob Agents Chemother, 2013, 57(7): 3182-3193.
[3] Chandra J, Kuhn DM, Mukherjee PK, et al. Biofilm formation by the fungal pathogen Candida albicans: development, architecture, and drug resistance[J].J Bacteriol, 2001, 183(18): 5385-5394.
[4] Cowen LE, Lindquist S. Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi[J]. Science, 2005, 309(5744): 2185-2189.
[5] Coste A, Turner V, Ischer F, et al. 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[J]. Genetics, 2006, 172(4): 2139-2156.
[6] Liu TT, Znaidi S, Barker KS, et al. Genome-wide expression and location analyses of the Candida albicans Tac1p regulon[J]. Eukaryotic cell, 2007, 6(11): 2122-2138.
[7] Coste AT, Crittin J, Bauser C, et al. Functional analysis of cis-and trans-acting elements of the Candida albicans CDR2 promoter with a novel promoter reporter system[J]. Eukaryotic cell, 2009, 8(8): 1250-1267.
[8] Morio F, Pagniez F, Besse M, et al. Deciphering azole resistance mechanisms with a focus on transcription factor-encoding genes TAC1, MRR1 and UPC2 in a set of fluconazole-resistant clinical isolates of Candida albicans[J].Int J Antimicrob Agents, 2013, 42(5): 410-415.
[9] Rustad TR, Stevens DA, Pfaller MA, et al. Homozygosity at the Candida albicans MTL locus associated with azole resistance[J]. Microbiology, 2002, 148(4): 1061-1072.
[10] Coste A, Selmecki A, Forche A, et al. Genotypic evolution of azole resistance mechanisms in sequential Candida albicans isolates[J]. Eukaryotic cell, 2007, 6(10): 1889-1904.
[11] Selmecki A, Gerami-Nejad M, Paulson C, et al. An isochromosome confers drug resistance in vivo by amplification of two genes, ERG11 and TAC1[J].Mol Microbiol, 2008, 68(3): 624-641.
[12] Chen CG, Yang YL, Shih HI, et al. CaNdt80 is involved in drug resistance in Candida albicans by regulating CDR1[J].Antimicrob Agents Chemother, 2004, 48(12): 4505-4512.
[13] Sellam A, Tebbji F, Nantel A. Role of Ndt80p in sterol metabolism regulation and azole resistance in Candida albicans[J]. Eukaryotic cell, 2009, 8(8): 1174-1183.
[14] Sellam A, Askew C, Epp E, et al. Role of transcription factor CaNdt80p in cell separation, hyphal growth, and virulence in Candida albicans[J]. Eukaryotic cell, 2010, 9(4): 634-644.
[15] Sasse C, Schillig R, Dierolf F, et al. The transcription factor Ndt80 does not contribute to Mrr1-, Tac1-, and Upc2-mediated fluconazole resistance in Candida albicans[J]. PloS one, 2011, 6(9): e25623.
[16] Wang JS, Yang YL, Wu CJ, et al. The DNA-binding domain of CaNdt80p is required to activate CDR1 involved in drug resistance in Candida albicans[J].J Med Microbiol, 2006, 55(10): 1403-1411.
[17] Yang YL, Wang CW, Leaw SN, et al. R432 is a key residue for the multiple functions of Ndt80p in Candida albicans[J]. Cellular and Molecular Life Sciences, 2012, 69(6): 1011-1023.
[18] Schillig R, Morschhuser J. Analysis of a fungus-specific transcription factor family, the Candida albicans zinc cluster proteins, by artificial activation[J]. Mol Microbiol, 2013, 89(5): 1003-1017.
[19] MacPherson S, Akache B, Weber S, et al. Candida albicans zinc cluster protein Upc2p confers resistance to antifungal drugs and is an activator of ergosterol biosynthetic genes[J].Antimicrob Agents Chemother, 2005, 49(5): 1745-1752.
[20] Oliver BG, Song JL, Choiniere JH, et al. cis-Acting elements within the Candida albicans ERG11 promoter mediate the azole response through transcription factor Upc2p[J]. Eukaryotic cell, 2007, 6(12): 2231-2239.
[21] Heilmann CJ, Schneider S, Barker KS, et al. An A643T mutation in the transcription factor Upc2p causes constitutive ERG11 upregulation and increased fluconazole resistance in Candida albicans[J].Antimicrob Agents Chemother, 2010, 54(1): 353-359.
[22] Dunkel N, Liu TT, Barker KS, et al. 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[J]. Eukaryotic cell, 2008, 7(7):1180-1190.
[23] Hoot SJ, Smith AR, Brown RP, et al. An A643V amino acid substitution in Upc2p contributes to azole resistance in well-characterized clinical isolates of Candida albicans[J].Antimicrob Agents Chemother, 2011, 55(2): 940-942. [24]Flowers SA, Barker KS, Berkow EL, et al. Gain of function mutations in UPC 2 are a frequent cause of ERG 11 upregulation in azole resistant clinical isolates of Candida albicans [J]. Eukaryotic cell, 2012, 11(10): 1289-1299.
[25]Znaidi S, Weber S, Al Abdin OZ, et al. Genomewide location analysis of Candida albicans Upc2p, a regulator of sterol metabolism and azole drug resistance[J]. Eukaryotic cell, 2008, 7(5): 836-847.
[26]Dunkel N, Bla J, Rogers PD, et al. Mutations in the multi drug resistance regulator MRR 1, followed by loss of heterozygosity, are the main cause of MDR 1 overexpression in fluconazole resistant Candida albicans strains[J]. Molecular microbiology, 2008, 69(4): 827-840.
[27]Morschhuser J, Barker KS, Liu TT, et al. The transcription factor Mrr1p controls expression of the MDR 1 efflux pump and mediates multidrug resistance in Candida albicans [J]. PLoS pathogens, 2007, 3(11): e164.
[28]Alarco AM, Raymond M. The bZip transcription factor Cap1p is involved in multidrug resistance and oxidative stress response in Candida albicans [J].J Bacteriol,1999,181(3):700-708.
[29]Riggle PJ, Kumamoto CA. Transcriptional regulation of MDR 1, encoding a drug efflux determinant, in fluconazole resistant Candida albicans strains through an Mcm1p binding site[J]. Eukaryotic cell, 2006, 5(12): 1957-1968.
[30]Mogavero S, Tavanti A, Senesi S, et al. Differential requirement of the transcription factor Mcm1 for activation of the Candida albicans multidrug efflux pump MDR 1 by its regulators Mrr1 and Cap1[J]. Antimicrobial agents and chemotherapy, 2011, 55(5): 2061-2066.
[31]Askew C, Sellam A, Epp E, et al. The zinc cluster transcription factor Ahr1p directs Mcm1p regulation of Candida albicans adhesion[J]. Molecular microbiology, 2011, 79(4): 940-953.
[32]Schubert S, Barker KS, Znaidi S, et al. Regulation of efflux pump expression and drug resistance by the transcription factors Mrr1, Upc2, and Cap1 in Candida albicans [J]. Antimicrobial agents and chemotherapy, 2011, 55(5): 2212-2223.