真菌多药耐药外排机制的研究进展

康烨; 周密; 阎澜

doi:10.3969/j.issn.1006-0111.2016.06.002

真菌多药耐药外排机制的研究进展

doi: 10.3969/j.issn.1006-0111.2016.06.002

康烨¹,
周密²,
阎澜^3,

1.
原沈阳军区总医院北陵临床部, 辽宁沈阳 110031
2.
解放军152医院, 河南平顶山 467000
3.
第二军医大学药学院新药研究中心, 上海 200433

基金项目: 国家自然科学基金面上项目（81470158）

Progress of the drug efflux mechanisms underlying fungi multidrug resistance

KANG Ye¹,
ZHOU Mi²,
YAN Lan^3
,

1.
Beiling Clinical Department, General Hospital of Shenyang Military Region, Shenyang 110031, China
2.
No. 152 Hospital of PLA, Pingdingshan 467000, China
3.
New Drug Research and Development Center, School of Pharmacy, Second Military Medical University, Shanghai 200433, China

摘要: 真菌多药耐药性是指真菌细胞对结构不同、作用靶点不同的药物同时具有耐药性的现象，是导致临床抗真菌治疗失败的重要原因之一。本文综述了酿酒酵母、条件致病真菌白假丝酵母、光滑假丝酵母和烟曲霉中多药耐药相关转运蛋白、药物外排机制以及基因表达调控网络的研究进展，旨在为深入了解真菌多药耐药性的机制、探讨克服多药耐药性的策略和提高抗真菌药物的药效提供参考。
- 真菌 /
- 多药耐药 /
- 外转运蛋白
Abstract: The multidrug resistance (MDR), characterized by the simultaneous acquisition of resistance to chemically and structurally different drugs, has caused antifungal treatment failure. This review focused on recent progresses in understanding of the multidrug resisitance associated drug efflux transporter superfamily in Saccharomyces cerevisiae, the opportunistic fungal pathogens Candida albicans, Candida glabrata, and Aspergillus fumigates, along with the mechanisms underlying efflux pump and the regulatory networks involved. Investigation of these mechanisms and their impact on drug resistance may lead to strategies to overcome fungal multidrug resistance and improvement of drug efficacy.
- fungus /
- multidrug resistance /
- multidrug efflux transporters

[1]	Morschhauser J. Regulation of multidrug resistance in pathogenic fungi[J]. Fungal Genet Biol,2010,47(2):94-106.
[2]	Ernst R, Kueppers P, Stindt J, et al. Multidrug efflux pumps:substrate selection in ATP-binding cassette multidrug efflux pumps——first come, first served?[J]FEBS J,2010,277(3):540-549.
[3]	Cannon RD, Lamping E, Holmes AR, et al. Efflux-mediated antifungal drug resistance[J]. Clin Microbiol Rev,2009,22(2):291-321.
[4]	Prasad R, Goffeau A. Yeast ATP-binding cassette transporters conferring multidrug resistance[J]. Annu Rev Microbiol,2012,66:39-63.
[5]	Simonics T, Kozovska Z, Michalkova-Papajova D, et al. Isolation and molecular characterization of the carboxy-terminal pdr3 mutants in Saccharomyces cerevisiae[J]. Curr Genet,2000,38(5):248-255.
[6]	Bosis E, Salomon D, Ohayon O,et al. Ssz1 restores endoplasmic reticulum-associated protein degradation in cells expressing defective cdc48-ufd1-npl4 complex by upregulating cdc48[J]. Genetics,2010,184(3):695-706.
[7]	Ducett JK, Peterson FC, Hoover LA, et al. Unfolding of the C-terminal domain of the J-protein Zuo1 releases autoinhibition and activates Pdr1-dependent transcription[J]. J Mol Biol,2013,425(1):19-31.
[8]	Prunuske AJ, Waltner JK, Kuhn P, et al. Role for the molecular chaperones Zuo1 and Ssz1 in quorum sensing via activation of the transcription factor Pdr1[J]. Proc Natl Acad Sci USA,2012,109(2):472-427.
[9]	Kolaczkowska A, Manente M, Kolaczkowski M, et al. The regulatory inputs controlling pleiotropic drug resistance and hypoxic response in yeast converge at the promoter of the aminocholesterol resistance gene RTA1[J]. FEMS Yeast Res,2012,12(3):279-292.
[10]	Teixeira MC, Dias PJ, Simoes T, et al. Yeast adaptation to mancozeb involves the up-regulation of FLR1 under the coordinate control of Yap1, Rpn4, Pdr3, and Yrr1[J]. Biochem Biophys Res Commun,2008,367(2):249-255..
[11]	Gulshan K, Schmidt JA, Shahi P, et al. Evidence for the bifunctional nature of mitochondrial phosphatidylserine decarboxylase:role in Pdr3-dependent retrograde regulation of PDR5 expression[J]. Mol Cell Biol,2008,28(19):5851-5864.
[12]	Teixeira MC, Cabrito TR, Hanif ZM, et al. Yeast response and tolerance to polyamine toxicity involving the drug:H+ antiporter Qdr3 and the transcription factors Yap1 and Gcn4[J]. Microbiology,2011,157(Pt 4):945-956.
[13]	Azie N, Neofytos D, Pfaller M, et al. The PATH (Prospective Antifungal Therapy) Alliance ^® registry and invasive fungal infections:update 2012[J]. Diagn Microbiol Infect Dis,2012,73(4):293-300.
[14]	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.
[15]	Mandal A, Kumar A, Singh A, et al. A key structural domain of the Candida albicans Mdr1 protein[J]. Biochem J,2012,445(3):313-322.
[16]	Shah AH, Singh A, Dhamgaye S, et al. Novel role of a family of major facilitator transporters in biofilm development and virulence of Candida albicans[J]. Biochem J,2014,460(2):223-235.
[17]	Li R, Kumar R, Tati S, et al. Candida albicans flu1-mediated efflux of salivary histatin 5 reduces its cytosolic concentration and fungicidal activity[J]. Antimicrob Agents Chemother,2013,57(4):1832-1839.
[18]	Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines for the management of candidiasis:2009 update by the Infectious Diseases Society of America[J]. Clin Infect Dis,2009,48(5):503-535.
[19]	Torelli R, Posteraro B, Ferrari S, et al. The ATP-binding cassette transporter-encoding gene CgSNQ2 is contributing to the CgPDR1-dependent azole resistance of Candida glabrata[J]. Mol Microbiol,2008,68(1):186-201.
[20]	Paul S, Schmidt JA, Moye-Rowley WS. Regulation of the CgPdr1 transcription factor from the pathogen Candida glabrata[J]. Eukaryot Cell,2011,10(2):187-197.
[21]	Brun S, Dalle F, Saulnier P, et al. Biological consequences of petite mutations in Candida glabrata[J]. J Antimicrob Chemother,2005,56(2):307-314.
[22]	Costa C, Pires C, Cabrito TR, et al. Candida glabrata drug:H+ antiporter CgQdr2 confers imidazole drug resistance, being activated by transcription factor CgPdr1[J]. Antimicrob Agents Chemother,2013,57(7):3159-3167.
[23]	Costa C, Nunes J, Henriques A, et al. Candida glabrata drug:H+ antiporter CgTpo3(ORF CAGL0I10384g):role in azole drug resistance and polyamine homeostasis[J]. J Antimicrob Chemother,2014,69(7):1767-1776.
[24]	Denning DW, Pleuvry A, Cole DC. Global burden of allergic bronchopulmonary aspergillosis with asthma and its complication chronic pulmonary aspergillosis in adults[J]. Med Mycol,2013,51(4):361-370.
[25]	Pound MW, Townsend ML, Dimondi V, et al. Overview of treatment options for invasive fungal infections[J]. Med Mycol,2011,49(6):561-580.
[26]	Snelders E, van der Lee HA, Kuijpers J, et al. Emergence of azole resistance in Aspergillus fumigatus and spread of a single resistance mechanism[J]. PLoS Med,2008,5(11):e219.
[27]	Chowdhary A, Kathuria S, Xu J, et al. Clonal expansion and emergence of environmental multiple-triazole-resistant Aspergillus fumigatus strains carrying the TR(3)(4)/L98H mutations in the cyp51A gene in India[J]. PloS one,2012,7(12):e52871.
[28]	Bueid A, Howard SJ, Moore CB, et al. Azole antifungal resistance in Aspergillus fumigatus:2008 and 2009[J]. J Antimicrob Chemother,2010,65(10):2116-2118.
[29]	Escribano P, Pelaez T, Munoz P, et al. Is azole resistance in Aspergillus fumigatus a problem in Spain?[J] Antimicrob Agents Chemother,2013,57(6):2815-2820.
[30]	Kovalchuk A, Driessen AJ. Phylogenetic analysis of fungal ABC transporters[J]. BMC genomics,2010,11:177.
[31]	Rajendran R, Mowat E, McCulloch E, et al. Azole resistance of Aspergillus fumigatus biofilms is partly associated with efflux pump activity[J]. Antimicrob Agents Chemother,2011,55(5):2092-2097.
[32]	Bowyer P,Mosquera J,Anderson M,et al.Identification of novel genes conferring altered azole susceptibility in Aspergillus fumigatus[J].FEMS Microbiol Lett,2012,332(1):10-19.
[33]	Qiao J, Liu W, Li R. Truncated Afyap1 attenuates antifungal susceptibility of Aspergillus fumigatus to voriconazole and confers adaptation of the fungus to oxidative stress[J]. Mycopathologia,2010,170(3):155-160.

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真菌多药耐药外排机制的研究进展

doi: 10.3969/j.issn.1006-0111.2016.06.002

Progress of the drug efflux mechanisms underlying fungi multidrug resistance

计量

真菌多药耐药外排机制的研究进展

doi: 10.3969/j.issn.1006-0111.2016.06.002

1. 原沈阳军区总医院北陵临床部, 辽宁沈阳 110031

2. 解放军152医院, 河南平顶山 467000

3. 第二军医大学药学院新药研究中心, 上海 200433

English Abstract

Progress of the drug efflux mechanisms underlying fungi multidrug resistance

1. Beiling Clinical Department, General Hospital of Shenyang Military Region, Shenyang 110031, China

2. No. 152 Hospital of PLA, Pingdingshan 467000, China

3. New Drug Research and Development Center, School of Pharmacy, Second Military Medical University, Shanghai 200433, China

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留言板

真菌多药耐药外排机制的研究进展

doi: 10.3969/j.issn.1006-0111.2016.06.002

Progress of the drug efflux mechanisms underlying fungi multidrug resistance

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出版历程

真菌多药耐药外排机制的研究进展

doi: 10.3969/j.issn.1006-0111.2016.06.002

1. 原沈阳军区总医院北陵临床部, 辽宁 沈阳 110031 2. 解放军152医院, 河南 平顶山 467000 3. 第二军医大学药学院新药研究中心, 上海 200433

English Abstract

Progress of the drug efflux mechanisms underlying fungi multidrug resistance

1. Beiling Clinical Department, General Hospital of Shenyang Military Region, Shenyang 110031, China 2. No. 152 Hospital of PLA, Pingdingshan 467000, China 3. New Drug Research and Development Center, School of Pharmacy, Second Military Medical University, Shanghai 200433, China

全文HTML

目录

1. 原沈阳军区总医院北陵临床部, 辽宁沈阳 110031

2. 解放军152医院, 河南平顶山 467000

3. 第二军医大学药学院新药研究中心, 上海 200433

1. Beiling Clinical Department, General Hospital of Shenyang Military Region, Shenyang 110031, China

2. No. 152 Hospital of PLA, Pingdingshan 467000, China

3. New Drug Research and Development Center, School of Pharmacy, Second Military Medical University, Shanghai 200433, China