Abstract:Gene CaMDR1 is a member of the major facilitator superfamily (MFS), mediating multidrug resistance of Candida albicans, and can confer resistance to benomyl, fluconazole and so forth. In this review, the progress in structure and function of the protein code by gene CaMDR1 and the transcriptional regulation mechanisms of CaMDR1 are summarized.
[1] Liu J, Shi C, Wang Y, et al. Mechanisms of azole resistance in Candida albicans clinical isolates from Shanghai, China[J]. Res Microbiol, 2015, 166(3): 153-161. doi:10.1016/j.resmic.2015.02.009 [2] Wirsching S, Michel S, Morschh user J. Targeted gene disruption in Candida albicans wild-type strains: the role of the MDR1 gene in fluconazole resistance of clinical Candida albicans isolates[J]. Mol Microbiol, 2000, 36(4): 856-865. doi:10.1046/j.1365-2958.2000.01899.x [3] Fling MF, Kopf J, Tamarkin A, et al. Analysis of a Candida abicans gene that encodes a novel mechanism for resistance to benomyl and methotrexate[J]. Mol Gen Genet, 1991(227): 318-329. doi:10.1007/BF00259685 [4] Goldway M, Teff D, Schmidt R, et al. Multidrug resistance in Candida albicans : disruption of the BENr gene[J]. Antimicrob Agents Chemother, 1995, 39(2): 422-426. doi:10.1128/AAC.39.2.422 [5] Rognon B, Kozovska Z, Coste AT, et al. Identification of promoter elements responsible for the regulation of MDR1 from Candida albicans , a major facilitator transporter involved in azole resistance[J]. Microbiology, 2006, 152(12): 3701-3722. doi:10.1099/mic.0.29277-0 [6] Wirsching S, Michel S, Ko Hler G, et al. 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]. J Bacteriol, 2000, 182(2): 400-404. doi:10.1128/JB.182.2.400-404.2000 [7] Hiller D, Sanglard D, Morschha User J. Overexpression of the MDR1 gene is sufficient to confer increased resistance to toxic compounds in Candida albicans [J]. Antimicrob Agents Chemother, 2006, 50(4): 1365-1371. doi:10.1128/AAC.50.4.1365 [8] Ying Y, Zhao Y, Hu X, et al. In vitro fluconazole susceptibility of 1,903 clinical isolates of Candida albicans and the identification of ERG11 mutations[J]. Microbial Drug Resist, 2013, 19(4): 266-273. doi:10.1089/mdr.2012.0204 [9] Mandal A, Kumar A, Singh A, et al. A key structural domain of the Candida albicans Mdr1 protein[J]. Biochemical J, 2012, 445(3): 313-322. doi:10.1042/BJ20120190 [10] Redhu AK, Khandelwal NK, Banerjee A, et al. pHluorin enables insights into the transport mechanism of antiporter Mdr1: R215 is critical for drug/H+ antiport[J]. Biochemical J, 2016, 473(19): 3127-3145. doi:10.1042/BCJ20160407 [11] Sun N, Li D, Fonzi W, et al. Multidrug-resistant transporter Mdr1p-mediated uptake of a novel antifungal compound[J]. Antimicrobial Agents Chemother, 2013, 57(12): 5931-5939. doi:10.1128/AAC.01504-13 [12] Watamoto T, Samaranayake LP, Egusa H, et al. Transcriptional regulation of drug-resistance genes in Candida albicans biofilms in response to antifungals[J]. J Medical Microbiol, 2011, (60): 1241-1247. doi:10.1099/jmm.0.030692-0 [13] Feng W, Yang J, Pan Y, et al. The correlation of virulence, pathogenicity, and itraconazole resistance with SAP activity in Candida albicans strains[J]. Canadian J Microbiol, 2016, 62(2): 173-178. doi:10.1139/cjm-2015-0457 [14] Bruzual I, Kumamoto CA. An MDR1 promoter allele with higher promoter activity is common in clinically isolated strains of Candida albicans [J]. Mol Genet Genomics, 2011, 286(5/6):347-357. doi:10.1007/s00438-011-0650-z [15] Sasse C, Schillig R, Reimund A, et al. Inducible and constitutive activation of two polymorphic promoter alleles of the Candida albicans multidrug efflux pump MDR1[J]. Antimicrob Agents Chemother, 2012, 56(8): 4490-4494. doi:10.1128/AAC.00264-12 [16] Morschh user M, Barker KS, Liu TT, et al. The transcription factor Mrr1p controls expression of the MDR1 efflux pump and mediates multidrug resistance in Candida albicans [J]. PLoS Pathog, 2007, 3(11): e164. doi:10.1371/journal.ppat.0030164 [17] Dunkel N, Bla J, Rogers PD, et al. 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[J]. Mol Microbiol, 2008, 69(4): 827-840. doi:10.1111/j.1365-2958.2008.06309.x [18] 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. doi:10.1128/AAC.00555-13 [19] 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]. Intl J Antimicrob Agents, 2013, 42(5): 410-415. doi:10.1016/j.ijantimicag.2013.07.013 [20] Schubert S, Popp C, Rogers PD, et al. Functional dissection of a Candida albicans zinc cluster transcription factor, the multidrug resistance regulator Mrr1[J]. Eukaryotic Cell, 2011, 10(8): 1110-1121. doi:10.1128/EC.05100-11 [21] Mogavero S, Tavanti A, Senesi S, et al. Differential requirement of the transcription factor Mcm1 for activation of the Candida albicans multidrug efflux pump MDR1 by its regulators Mrr1 and Cap1[J]. Antimicrob Agents Chemother, 2011, 55(5): 2061-2066. doi:10.1128/AAC.01467-10 [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. doi:10.1128/EC.00103-08 [23] 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]. Antimicrob Agents Chemother, 2011, 55(5): 2212-2223. doi:10.1128/AAC.01343-10 [24] Alarco A M, 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. [25] Tan PL, Wang ZJ, Zhao JF. Resistance of Candida albicans isolates against fluconazole and the resistance correlation with CAP 1 gene[J]. Chin J Zoonoses, 2015, 3(4): 325-329. doi:10.3969/cjz.j.issn.1002-2694.2015.04.007 (in Chinese) 谈潘莉, 汪浙炯, 赵金方. 白假丝酵母菌临床菌株对氟康唑耐药性及其与 CAP 1基因相关性研究[J]. 中国人兽共患病学报, 2015, 3(4): 325-329. [26] Ramirez-Zavala B, Mogavero S, Scholler E, et al. SAGA/ADA complex subunit Ada2 is required for Cap1- but not Mrr1-mediated upregulation of the Candida albicans multidrug efflux pump MDR1[J]. Antimicrob Agents Chemother, 2014, 58(9): 5102-5110. doi:10.1128/AAC.03065-14 [27] Znaidi S, Barker KS, Weber S, et al. Identification of the Candida albicans Cap1p regulon[J]. Eukaryotic Cell, 2009, 8(6): 806-820. doi:10.1128/EC.00002-09 [28] Chen C, Yang Y, Tseng K, et al. Rep1p negatively regulating MDR1 efflux pump involved in drug resistance in Candida albicans [J]. Fungal Genetics Biol, 2009, 46(9): 714-720. doi:10.1016/j.fgb.2009.06.003 [29] Lo H, Tseng K, Kao Y, et al. Cph1p negatively regulates MDR1 involved in drug resistance in Candida albicans [J]. Intl J Antimicrob Agents, 2015, 45(6): 617-621. doi:10.1016/j.ijantimicag.2015.01.017 [30] Ahmad A, Khan A, Manzoor N. Reversal of efflux mediated antifungal resistance underlies synergistic activity of two monoterpenes with fluconazole[J]. Europ J Pharmaceutic Sci, 2013, 48(1-2): 80-86. doi:10.1016/j.ejps.2012.09.016