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研究生:吳金蓉
論文名稱:研究白色念珠菌REP3突變株的功能性補救
論文名稱(外文):Study of REP3 (Regulator of Efflux Pump) functional rescue in rep3/rep3 homozygous mutants of Candida albicans
指導教授:楊昀良
學位類別:碩士
校院名稱:國立交通大學
系所名稱:生化工程研究所
學門:工程學門
學類:化學工程學類
論文種類:學術論文
論文出版年:2007
畢業學年度:95
語文別:英文
論文頁數:121
中文關鍵詞:白色念珠菌排藥幫浦異位調控因子藥物感受性啤酒酵母
外文關鍵詞:Candida albicansRegulator of Efflux Pumpdrug susceptibilitySaccharomyces cerevisiae
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伺機性病原菌—白色念珠菌 (Candida albicans) 是造成人體黴菌感染最常見的病原。Azole類藥物常用來治療白色念珠菌的感染。然而,廣泛使用fluconazole使得抗藥性白色念珠菌菌株之案例大增,進而導致臨床上治療失敗的機會增高。因此,瞭解白色念珠菌抗藥機轉對於克服黴菌感染是很重要的。排藥幫浦CDR1和CDR2的過量表現常見於抗藥性臨床菌株,然而其表現被如何調控卻所知甚少。實驗室先前經由在Saccharomyces cerevisiae 所進行之library screening 發現在白色念珠菌中,REP3 (Regulator of Efflux Pump) 能增加CDR1 Ym990348啟動子-lacZ 的 ��-galactosidase 活性約四倍。再者根據藥物敏感性測試的結果顯示REP3突變株對azole類藥物的感受性有提高的現象,但REP3 突變補救株對藥物感受性卻沒有恢復。本研究重新建構突變株,但結果仍同,經Real-time PCR檢測顯示REP3 mRNA 確實存在rep3/rep3::REP3 突變補救株中且表現量與野生株SC5314相近。意外的是,在rep3/rep3 突變株、rep3/rep3::REP3突變補救株及野生株SC5314中CDR1 的mRNA量相近。再者,在藥物誘導下,另一個距REP3基因下游處266 個核酸的orf19.3926表現量在rep3/rep3::REP3 突變補救株中比rep3/rep3 突變株及野生株提高了3.5倍。即使利用SAT1的策略再次重新建構rep3/rep3::REP3突變補救株,以減少額外載體DNA序列介入rep3/rep3 突變株中可能造成的干擾,仍然無法補救rep3/rep3 突變株對藥物敏感的表現型。由於在rep3/rep3 突變株中,CDR1 之mRNA並未下降,因此,對於REP3 是否透過其他非調控CDR1的路徑而影響白色念珠菌的藥物抗藥性,以及rep3突變株的功能難以補救回復的原因,將來需做更進一步的研究。
Candida albicans is an opportunistic fungal pathogen and is the most common cause of deep mycoses in humans. Azole therapy is commonly used to treat C. albicans infections. However the widespread use of azoles led to an increased frequency of treatment failure due to azole-resistant C. albicans in clinical setting. Therefore, understanding the molecular mechanisms of drug resistance in C. albicans is important to render the fungal infection. Over expression of drug efflux pumps— CDR1 and CDR2 (Candida Drug Resistance 1 and 2) in azole resistant C. albicans is commonly observed but the regulatory mechanism is poorly understood. Previously in the laboratory, REP3 (Regulator of Efflux Pump) was isolated from Candida genomic library due to its ability to increase the ��-galactosidase activity of CDR1YM990348 promoter-lacZ about four folds in Saccharomyces cerevisiae in the presence of miconazole. According to the results of the drug susceptibility tests, rep3/rep3 homozygous mutant seems to be more susceptible to miconazole, itraconazole, ketoconazole, fiuconazole and voriconazole than the SC5314 wild-type strain in spite of rep3/rep3::REP3 rescued strains not showing a restoration of drug susceptibility phenotype. In this study, REP3 rescued strains were re-constructed and the outcome remained the same. No REP3 mRNA could be detected in rep3/rep3 mutant and the real-time PCR results showed that the REP3 mRNA could be detected in the rep3/rep3::REP3 rescued strains in similar quantity as that of the SC5314 wild-type strain. Surprisingly, the expressions of CDR1 were similar in the rep3/rep3 mutants, rep3/rep3::REP3 rescued strains, and SC5314 wild type strain. Furthermore, the expression level of the orf19.3926, which locates at the down stream 266 bps from REP3, increased about 3.5 folds in the REP3 rescued strain than that of the wild-type strains and rep3/rep3 mutants in the presence of miconazole. Even though the REP3 rescued strains were reconstructed through SAT1 flipping method to eliminate the potential interference from the integration of vector DNA fragment in C. albicans, the regenerated rep3/rep3::REP3 rescued strains still cannot restore completely the drug susceptibility phenotype of rep3/rep3 mutant. Since the mRNA level of CDR1 in rep3/rep3 mutant was the same as that in the wild type. REP3 may be involved in drug resistance through pathways other than CDR1 in C. albicans. There is no clear reason as the why the rep3/rep3::REP3 rescued strain could not restore the REP3 phenotype. Both will require further studies.
Abstract (Chinese) i
Abstract (English) ii
Acknowledgement iv
Contents v
Contents (Figures) x
Contents (Tables) xiii
Chapter 1. Introduction 1
1.1 Clinical significance of Candida infection 1
1.2 Candida albicans is an opportunistic pathogen 2
1.3 Resistance of C. albicans to antifungal agents 3
1.4 Mechanism of resistance to azole antifungal agents 5
1.5 Candida drug resistance gene: CDR1 7
1.6 Cis- and trans-acting factors regulating of CDR genes 8
1.6.1 Cis-regulatory factors of efflux pumps involved in azole resistance 8
1.6.2 Trans-regulatory factors of efflux pumps involved in azole resistance 10
1.7 Previous work in the laboratory 11
1.8 The purpose of the study 12
Chapter 2. Materials and Methods 13
2.1 Materialsts 13
2.1.1 Strains 13
2.1.2 plasmids and primers 13
2.1.3 Chemicals and reagents 13
2.1.4 Buffers 15
2.1.5 Medium 16
2.1.6 Enzymes 17
2.1.7 Equipments 17
2.1.8 Strains and growth media 18
2.2 Methods 19
2.2.1 DNA methods 19
2.2.2 Preparing electrocompetent cells 19
2.2.3 E. coli. transformation with electroporation 20
2.2.4 Competent cell prepared using Calcium chloride 21
2.2.5 E. coli. transformation using Calcium chloride 21
2.2.6 Constructions of plasmids and strains 22
2.2.7 Complementation of the REP3 gene (CJC7 and CJC10)in rep3/rep3 mutant strains (CSC80 and CSC81) 23
2.2.8 Complementation of the REP3 gene (CJC13~CJC18)in rep3/rep3 his1::hisG/ his1:: hisG::HIS1 mutants (CJC2 and CJC4) by SAT1 method 24
2.2.9 The REP3 rescued strains (CJC13 ~ CJC18) excise the SAT1 flipping 25
2.2.10 Isolation of genomic DNA 26
2.2.11 Transformation of Candida albicans by lithium acetate method 27
2.2.12 Transformation of Candida albicans by electroporation method 28
2.2.13 Southern blot analysis 29
2.2.14 Antifungal susceptibility test with agar dilution assay 31
2.2.15 Antifungal susceptibility test with CLSI M-27A method 31
2.2.16 Isolation of RNA by the hot acid phenol method 32
2.2.17 Isolation of RNA by the Masterpure Yeast Purification Kit 34
2.2.18 Quantitative analysis of the mRNA level by real-time polymerase chain reaction (real-time PCR) 35
Chapter 3. Results 38
3.1 Generation of histidine prototrophy of rep3/rep3 mutant 38
3.2 The antifungal drugs susceptibility of histidine prototrophy rep3/rep3 is identical with h- istidine auxototrophy rep3/rep3 38
3.3 The REP3 rescued strains YLO221 and YLO222 cannot restore the drug susceptibility p- henotype of rep3/rep3 39
3.4 The REP3 sequence of the rescue plasmid (pWJB24) is identical with the REP3 sequenc- e of Candida Genome Database (CGD) 40
3.5 Re-construction the REP3 rescued strains (CJC7 ~ CJC12) with pWJB24 40
3.6 The REP3 was disrupted at the proper chromosomal location and the ARG4 or URA3 marker did not integrated into unpredicted chromosome locations 41
3.7 The REP3 rescued strains (CJC7 and CJC10) did not show a restored drug susceptibility phenotype of rep3/rep3 43
3.7.1 The agar dilution assay 43
3.7.2 Broth microdilution method (according to NCCLS standard) 44
3.8 Comparison of the genes expression level of rep3/rep3 mutants and the rescued strains (CJC7 and CJC10) in C- andida albicans 45
3.8.1 The expression of REP3 in wild type and rescued strains (CJC7 and CJC10) but not in knockout strains (CJC2 and CJC4) 45
3.8.2 Mutations in REP3 do not decrease the CDR1 expression 45
3.8.3 The expression level of orf19.3926 increased about 3.5 folds in the REP3 rescued strains than that of wild-type and rep3/rep3 in the presence of miconazole 46
3.9 Construction of the REP3 rescue plasmid (SATI flipping method) 46
3.9.1 Construction of A fragment into pSFS2 to create CJB1 ~ CJB5 46
3.9.2 Construction of CJB6 ~ CJB10: pGEM-T easy vector with B fragment 47
3.9.3 Comparison of the REP3 rescue plasmid sequence between pWJB24 and pCJB6 ~ pCJB8 47
3.9.4 Construction of the plasmid CJB11and CJB15 with A and B fragments on both sides of SAT1 from pSFS2 48
3.10 Construction and confirmung the rep3/rep3::REP3 (SATI flipping method) rescued str- ains (CJC13 ~ CJC18) 48
3.11 The REP3 rescued strains (SAT1 cassette method) (CJC19 ~ CJC24) can not show a restored phenotype of drug susceptibility 49
3.11.1 The agar dilution assay 49
3.11.2 Broth microdilution method (according to NCCLS standard) 50
Chapter 4. Discussion 51
4.1 Genomic organization of the REP3 locus 51
4.2 The phenotype of rescued strains 51
4.3 The relationship with drug resistance between trans-regulator factor, REP3 and CDR1 53
4.4 Other uncharacterized protein factors probably bind to elements within the MDR1 prom- oter and trans-activate the MDR1 gene 55
4.5 REP3 is a homolog of CRZ1, a target of the calcineurin pathway, in Candida albicans 56
4.6 Orf19.3926 has high similarity to uncharacterized Candida albicans Rny1p 58
Chapter 5. Future work 61
References 63
Tables 73
Figures 79
簡歷 121
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75. 紀錦昇Chin-Sheng Chi 2004
在藥物誘導下分離鑑定白色念珠菌之調控因子
Isolation and identification of trans-regulatory factors of CDR1 in Candida albicans.
Master thesis, Institute of Biological Science and Technology, National Chiao Tung University.
76. 吳宛真Wan-Jen Wu 2005
白色念珠菌抗藥基因CDR1 之異位調控因子REP3、REP4 與REP5之遺傳學研究
Genetic study of trans-regulatory factors REP3, REP4 and REP5 of the drug resistant gene CDR1 in Candida albicans.
Master thesis, Institute of Biological Science and Technology, National Chiao Tung University.
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