臺灣博碩士論文加值系統

PartI:
白色念珠菌 (Candida albicans) 是一種伺機性的致病黴菌, 會導致免疫力不全病人的死亡。有抗藥性的白色念珠菌因病人的頻繁使用抗黴菌藥物而被篩選出來。黴菌感染因免疫力不全病人數日益增加而成為院內感染的問題，因此，開發出低副作用的新抗黴菌藥物是一重要的課題。黴菌的細胞壁是一個很好的藥物標靶，因為哺乳動物的細胞並沒有這項胞器。而研究具有修飾細胞壁能力的酵素便是從事這種類新藥的基礎課題。在白色念珠菌中的葡聚糖酶 (glucanase) 則具有這種潛力，目前，至少有十一個可能的葡聚糖酶基因存在白色念珠菌中。cph1/cph1 efg1/efg1 的變異株不會生長菌絲，而且也不會造成實驗用小鼠的死亡。若能了解是那個葡聚糖酶與菌絲的生長有關，這個葡聚糖酶將可以做為抑制菌絲生長的標靶。首先、我偵測到類 1, 3-b-葡聚糖酶基因CaIPF885具有與其他基因不同型式的表現，它在野生株 (wild-type) SC5314 的表現量比在 cph1/cph1 efg1/efg1 變異株高。令人訝異的是，當完全移除白色念珠菌中的這個 CaIpf885p 時，並沒有觀察到其在菌絲生長，生物膜成形，及對一氧化氮和細胞壁染劑敏感度上和野生株有所差異，而且在生長速率上也和野生株 SC5314 一般並無軒輊。而且也無法偵測到融合型的表現蛋白 maltose binding protein-CaIpf885p (MBP-CaIpf885p) 有外切式葡聚糖酶 (exo-1, 3-b-glucanase) 的活性。有趣的是， Caipf885/ Caipf885 突變株對生物性清潔劑膽汁酸鹽 (bile salt) 中的去氧膽汁酸鹽 (sodium deoxycholate) 和鵝膽汁酸鹽 (sodium chenodeoxycholate)的感受性增加，而對鍵結型的其它鹽類則與 SC5314 一般並沒有太大差異，對其它生化上常用的人工清潔劑像 NP-40, Tween-20, Triton X-100, and Sodium dedocyl sulfate (SDS) 也無明顯差別。去氧膽汁酸鹽會誘導哺乳類動物細胞的淍亡 (Apoptosis)，文獻中記載了膽汁酸會抑制黴菌麥角醇 (ergosterol) 的合成，而在野生株 SC5314 上，我也觀察到了去氧膽汁酸鹽引起類似細胞淍亡的現象。CaIpf885p 在麥角醇合成及細胞淍亡間所扮演的角色需要再更進一步的探討。總而言之，我們打開了一扇連接去氧膽汁酸鹽與細胞淍亡間的窗，提供了一個發展治療感染性黴菌藥物的新思考方向。

PartII:
CaNdt80p 是白色念珠菌中與酵母菌的轉錄因子 ScNdt80p類似的蛋白質，也是白色念珠菌中與抗藥性有關的流出幫浦基因 CDR1 的正向調控者。我們構築了 CaNdt80p 和 ScNdt80p 的嵌合體藉以探究 CaNdt80p的 DNA 結合區域與抗藥性間的關聯性。CaNdt80p 的DNA 結合區域無法取代ScNdt80p 的DNA 結合區域在孢子萌發上的角色，有趣的是，ScNdt80p 的DNA 結合區域可以替代 CaNdt80p的結合區域活化 在酵母菌中的CDR1p-lacZ 之功能。具有一致性的是，在 DNA 結合區域含有單一點突變的CaNdt80p 並無法活化在酵母菌中的CDR1p-lacZ 。而且，在白色念珠菌中，一個在DNA 結合區域具有相同突變的 Candt80R432A 拷貝也無法補回因為CaNDT80 完全缺失後所造成的對藥物敏感的表現型。因此CaNdt80p 之 DNA 結合區域在白色念珠菌的抗藥性上扮演了關鍵的角色。

PartI:
Candida albicans is an opportunistic pathogen causing high mortality in immuno-compromised patient. The more and more antifungal drug resistant strains were isolated from nosocomial infections. Today, the development of new drugs with low side effects is the important issue. The cell wall is a good target for antifungal drug because the mammalian does not have such organelle. Thus, enzymes having the function to modify the components of cell wall are good target for designing new drugs. In C. albicans, I found at least 11 genes potentially encoding glucanases. The cph1/cph1 efg1/efg1 mutant is non-filamentous and avirulent in a mouse model. The glucanase involved in filament formation can be the good target for inhibiting the filamentous growth. I found that the expression of all genes tested except CaIPF885 in the wild-type strain, SC5314 cells was higher than that in the cph1/cph1 efg1/efg1 double mutant cells. Surprisingly, the CaIPF885 null mutant has neither the defect in hyphal and biofilm formation nor increasing sensitivity to cell wall binding dye and Nitric oxide (NO). The mutant cell grew as good as the wild-type strain. The exo-1, 3-b-glucanase activity was not detected in the maltose binding protein-CaIpf885p (MBP-CaIpf885p) fusion protein. Interestingly, mutations on the CaIPF885 gene dramatically increased the susceptibility to biological detergent, bile salt, such as, sodium deoxycholate (NaDOC) or sodium chenodeoxycholate but not to the conjugated form bile acids or other biochemical detergents, such as, NP-40, Tween-20, Triton X-100, and Sodium dedocyl sulfate (SDS). In vitro, the bile acids inhibit the synthesis of ergosterol in C. albicans. The NaDOC could bear the apoptosis-like response in C. albicans since it drives apoptosis in mammalian cells. The function of CaIpf885p related to synthesis of ergosterol and apoptosis need further investigation. In that, I found an exo-1, 3-b-glucanase-like gene bearing apoptosis-like response to NaDOC in C. albicans, which may open another door for the design of novel antifungal drugs.

PartII:
CaNdt80p, the Candida albicans homologue of the Saccharomyces cerevisiae transcription factor ScNdt80p, has been identified as a positive regulator of CDR1, encoding an efflux pump involved in drug resistance in C. albicans. To investigate the involvement of the putative DNA binding domain of CaNdt80p in drug resistance, we have constructed chimeras of CaNdt80p and ScNdt80p. The DNA binding domain of CaNdt80p could not complement the function of that of ScNdt80p in sporulation. Interestingly, the DNA binding domain of ScNdt80p could functionally complement that of CaNdt80p to activate CDR1p-lacZ in S. cerevisiae. Consistently, CaNdt80p containing a mutation in the DNA binding domain failed to activate the CDR1p-lacZ in S. cerevisiae. Furthermore, a copy of CaNDT80 with the same mutation also failed to complement the drug sensitive phenotype caused by a null mutation in C. albicans. Thus, the DNA binding domain of CaNdt80p is critical for its function in drug resistance in C. albicans.

PartI:
Table of contents (Part I)
Table of contents (Part I) I
Table of figures VI
Table of appendixes IX
中文摘要 X
Abstract XII
Introduction 1
1. Clinical significance of fungal infection. 1
2. Mechanisms of action of antifungal drugs. 2
2.1 Polyenes 3
2.2 Ergosterol biosynthesis inhibitors 3
2.3 Nucleic acid synthesis inhibitor 4
2.4 Cell wall synthesis inhibitor 5
2.5 Drugs under development 5
3. Biosynthesis of bile acids 6
4. The sodium deoxycholate (NaDOC) 7
5. Candida albicans 8
6. Cell wall structure of Candida albicans 9
7. 1, 3-b-glucanases in Candida albicans 11
7.1 Endo-1, 3-b-glucanase 12
7.1.1 CaBGL2 12
7.1.2 CaMP65 13
7.1.3 CaSCW4 14
7.1.4 CaSCW1 15
7.1.5 CaENG1 16
7.1.6 CaENG2 17
7.1.7 CaSCW10 17
7.2 Exo-1, 3-b-glucanase 18
7.2.1 CaEXG1 18
7.2.2 CaEXG2 19
7.2.3 CaSPR1 20
7.2.4 CaIPF885 21
8. Specific aims of the study 22
Material and Methods 23
1. Strains and media 23
2. Endo-1, 3-b-glucanase motif 23
3. Exo-1, 3-b-glucanase motif 24
4. DNA methods 24
5. Construction of the homozygous mutant strains of CaIPF885 25
6. Complementation of the Caipf885/Caipf885 deletion. 29
7. Construction of the homozygous mutant strains of CaEXG1. 29
8. Complementation of the Caexg1/Caexg1 deletion. 31
9. Construction of the of Caipf885/Caipf885 Caexg1/Caexg1 strain. 31
10. Complementation of either the CaIPF885 or the CaEXG1 gene in Caipf885/Caipf885 Caexg1/Caexg1 double knockout mutant. 34
11. Transformation of Candida albicans (lithium acetate method). 34
12. Escherichia coli transformation with electroporation. 36
13. Genomic DNA extraction. 36
14. Antifungal susceptibility tests. 38
15. Germ tube analysis. 39
16. Quantitative analysis of the mRNA level by real-time PCR. 40
16.1 The 10% horse serum treated SC5314 and cph1/cph1 efg1/efg1. 40
16.2 The 0.05% Sodium deoxycholate (NaDOC) treated the wild-type SC5314 strain. 41
17. Growth curve, survival curve and survival rate. 43
18. Chemical susceptibility test. 43
19. Growth inhibition assays. 44
20. Biofilm growth and CSLM images. 45
21. Small-scale protein induction. 46
22. Glucanase activity assay. 47
Results 48
1. 1, 3-b-glucanases in Candida albicans. 48
2. The expression pattern of 1, 3-b-glucanases in Candida albicans. 49
3. Construction of the Caipf885/Caipf885 mutant. 49
4. The phenotype of Caipf885/Caipf885 mutant. 50
5. The effect of NaDOC on wild type Candida albicans. 53
6. Construction of the Caexg1/Caexg1 and the Caipf885/Caipf885 Caexg1/Caexg1 mutants. 55
7. The Caipf885/Caipf885 Caexg1/Caexg1 double knockout strain had the similar phenotype as Caipf885/Caipf885. 56
9. The Caipf885/Caipf885 mutant was sensitive to specific bile salts but not very specific biochemical detergent. 58
10. The fusion protein MBP-CaIpf885p did not exhibit exo-1, 3-b-glucanase activity. 60
Discussion 61
1. Comparison of the phenotype of 1, 3-b-glucanase between Candida albicans and Saccharomyces cerevisiae. 61
1.1 Endo-1, 3-b-glucanase in Saccharomyces cerevisiae. 61
1.2 Exo-1, 3-b-glucanase in Saccharomyces cerevisiae. 62
2. The putative cis-element in CaIPF885. 65
3. The linkage of NaDOC and apoptosis in Candida albicans. 66
4. The possible roles of CaIpf885p in Candida albicans. 69
4.1 In the function for change the cell membrane or cell wall. 70
4.2 There may be exhibit the possible that CaIpf885p accelerate the efflux pump for export the NaDOC. 71
4.3 The real pathway for NaDOC bear the apoptosis-like response in Candida albicans is unclear. 71
5. The expression of CaMCA1 is not increased after treated with NaDOC. 73
6. The biochemical function of CaIpf885p. 74
Future works 76
1. To confirm the apoptosis response after treated with NaDOC. 76
2. To analysis the cell wall components and morphology under the electron microscopy. 76
3. To determine the biological functions of CaIpf885p 76
4. The concentration NaDOC and ergosterol in C. albicans after treatment. 77
5. To monitor the transcript expression of other glucanase and ergosterol synthesis related genes. 77
References 78

Table of tables
Table 1. Bacteria (Escherichia coli) and Candida albicans used in this study. 93
Table 2. Plasmids used in this study. 96
Table 3. Primers used in this study. 97
Table 4. The 1, 3-b-glucanase genes in Candida albicans. 101
Table 5. The transcription profiles of 1, 3-b-glucanase genes in Candida albicans. 102
Table 6. D.T. (Doubling time) 103
Table 7. Transcription profiles in the absence or presence of 0.05% NaDOC in SC5314. 104
Table 8. Putative cis-acting sites in the CaIPF885 promoter. 105


Table of figures
Fig. 1. There are five proteins having the motif of endo-1, 3-b-glucanase. 106
Fig. 2. CaIpf885p has the incomplete motif of exo-1, 3-b-glucanase. 107
Fig. 3. Construction of the Caipf885/Caipf885 mutant. 108
Fig. 4. Complementation of the Caipf885/Caipf885 deletion. 109
Fig. 5. Construction of the Caexg1/Caexg1 mutant. 110
Fig. 6. Complementation of the Caexg1/Caexg1 deletion. 111
Fig. 7. Lost the URA3 marker from Caipf885/Caipf885 mutant. 112
Fig. 8. Construction of the CaEXG1/Caexg1 Caipf885/Caipf885 mutant. 113
Fig. 9. Lost the URA3 marker from Caipf885/Caipf885 CaEXG1/Caexg1 mutant. 114
Fig. 10. Construction of the Caexg1/Caexg1 Caipf885/Caipf885 double knockout mutant. 115
Fig. 11. Complementation of the Caexg1/Caexg1 or Caipf885/Caipf885 deletion in double knockout strains. 116
Fig. 12. The transcripts of CaIPF885 are detected in wild type and rescued strains but not in knockout strains. 117
Fig. 13. The germ tube formation and filamentous grown is normal on the Caipf885/Caipf885 mutant. 118
Fig. 14. CSLM images of biofilms stained with calcofluor white. 119
Fig. 15. Deletion of CaIPF885 does not increase the sensitivity to sodium nitrite (NaNO2). 120
Fig. 16. Deletion on CaIPF885 does not increase sensitivity to zymolyase. 121
Fig. 17. Deletion on CaIPF885 does not increase sensitivity to the chemical of cell wall integrity test in the agar assay. 122
Fig. 18. Susceptibility to drug determining by Etest assay. 123
Fig. 19. Effect of sodium deoxycholate (NaDOC) on the growth of Caipf885/Caipf885 mutant. 124
Fig. 20. Deletion of CaIPF885 increased the sensitivity to sodium deoxycholate (NaDOC). 125
Fig. 21. Micrographs of the cells grow in the presence of 0.1% NaDOC. 126
Fig. 22. The different concentrations of NaDOC on the growth of wild-type SC5314 cells. 127
Fig. 23. Micrographs of the wild-type SC5314 cells grow in the presence of 0.05% NaDOC. 128
Fig. 24. DNA smearing pattern of Candida albicans cells treated with H2O or 0.1% NaDOC at different time points. 129
Fig. 25. The transcripts of CaEXg1 and CaIPF885 could not be detected in knockout strains. 130
Fig. 26. Susceptibility to drug determining by Etest assay. 131
Fig. 27. The survival curve after treated by sodium deoxycholate (NaDOC) of C. albicans. 132
Fig. 28. The survival rate of Candida albicans grown in treated with 0.05% sodium deoxycholate (NaDOC) at different time points. 133
Fig. 29. Deletion on CaIPF885 does not increase susceptibility to other detergents in the agar assay. 134
Fig. 30. Mutations on CaIPF885 increase susceptibility to NaDOC and chenodeoxycholate but not other bile acids in the agar assay. 135
Fig. 31. Mutations on CaIPF885 increase susceptibility to NaDOC and chenodeoxycholate but not other bile acids in the agar assay. 136
Fig. 32. CaIpf885p is inducing by 1 mM IPTG in E. coli strains. 137
Fig. 33. The exo-1, 3-b-glucanase-activity test of CaIpf885p by agar disc assay. 138
Fig. 34. The location of catalytic residue (glutamate, E) of CaExg1p and CaIpf885p. 139


Table of appendixes
Appendix 1. Primary and secondary bile acids included ionic and conjugated forms. 140
Appendix 2. A model of architecture of the yeast cell wall. 141
Appendix 3. Critical micelle concentration (CMC) of bile salts. 142
Appendix 4. Possible molecular mechanisms of antifungal agent resistance. 143
Appendix 5. The alternate pathway. 144

PartII:
Table of contents (Part II)
Table of contents (Part II) XIV
Table of tables XVII
Table of figures XVIII
中文摘要 XIX
Abstracts XX
Introduction 145
1. Molecular mechanisms of azoles resistance. 145
2. Overexpression of genes encoding efflux pumps to decrease accumulation of drug. 146
3. Regulation of the CDR1 gene. 147
3.1 Cis-element 147
3.2 Trans-activator 148
4. Function of CaNdt80p in drug resistant in Candida albicans. 148
5. Function of ScNdt80p in meiosis in Saccharomyces cerevisiae. 149
6. The purpose of the study. 150
Materials and Methods 151
1. Strains and media. 151
2. Domain swapping (construction of plasmid and strains). 151
2.1 LOB114 (pRS426-CaNDT80pro-CaNDT80-AD-ScNDT80-BD) 151
2.2 LOB115 (pRS426-CaNDT80pro-CaNDT80-AD) 152
2.3 LOB116 (pRS426-CaNDT80pro-ScNDT80-BD-ScNDT80-AD) 153
2.4 LOB117 (pRS426-CaNDT80pro-CaNDT80-AD-ScNDT80-BD-ScNDT80-AD) 153
2.5 BS88 (pRS426-ScNDT80pro-CaNDT80-BD- ScNDT80-AD) 154
2.6 LOB46 (pRS426-ScNDT80 was constructed by Ming-Yang Tsao) 155
3. In vitro assay of b-galactosidase activity. 156
4. Reverse transcription-polymerase chain reaction. 157
5. Quantitative analysis of the mRNA level by Real-Time PCR. 158
6. Site-directed mutagenesis. 159
7. Transformation of Saccharomyces cerevisiae (lithium acetate method) 160
8. Drug susceptibility tests. 161
9. Sporulation assay 162
Results 163
1. ScNdt80p failed to activate CDR1p-lacZ in Saccharomyces cerevisiae. 163
2. The DNA binding domain of ScNdt80p can functionally complement that of CaNdt80p in Saccharomyces cerevisiae. 164
3. CaNdt80p with a mutation on the DNA binding domain failed to activate CDR1p-lacZ in Saccharomyces cerevisiae. 165
4. Construction of the Candt80/Candt80::Candt80 R432A Candida albicans strain. 165
5. The Candt80R432A allele with a mutation on the DNA binding domain failed to complement the Candt80/Candt80 mutant cells. 166
6. The CaNDT80-BD failed to complement the ScNDT80-BD in spore formation. 168
Discussion 170
1. ScNdt80p failed to activate CDR1p-lacZ in Saccharomyces cerevisiae. 170
2. The DNA binding domain of ScNdt80p can functionally complement that of CaNdt80p in Saccharomyces cerevisiae. 170
3. The Candt80R432A allele with a mutation on the DNA binding domain failed to complement the Candt80/Candt80 mutant cells. 171
4. The C-terminal putative DNA binding domain of CaNdt80p failed to complement the DNA binding domain of ScNdt80p in spore formation. 171
Conclusion 173
Future works 174
References 175

Table of tables
Table 1. Saccharomyces cerevisiae used in this study. 179
Table 2. Candida albicans used in this study. 180
Table 3. Plasmids used in this study. 181
Table 4. Primers used in this study. 182


Table of figures
Fig. 1. Comparison of CaNdt80p in C. albicans and ScNdt80p in S. cerevisiae. 184
Fig. 2. Different chimeras having different effects on the expression of the CDR1p–lacZ reporter in S. cerevisiae. 185
Fig. 3. Expression of different chimeras in S. cerevisiae and both CaNDT80 and Candt80R432A alleles in C. albicans. 186
Fig. 4. Susceptibility to drug amphotericin B was determined by Etest assay. 187
Fig. 5. Susceptibility to azole drug ketoconazole was determined by Etest assay. 188
Fig. 6. Susceptibility to azole drug itroconazole was determined by Etest assay. 189
Fig. 7. Susceptibility to azole drug voriconazole was determined by Etest assay. 190
Fig. 8. Susceptibility to azole drug fluconazole was determined by Etest assay. 191
Fig. 9. The Candt80R432A allele failed to complement Candt80/Candt80 mutant cells. 192
Fig. 10. The CaNDT80-BD (DNA binding domain) failed to complement the ScNDT80-BD in sporulation assay. 193
Fig. 11. Comparison of ScNdt80p and chimera protein in S. cerevisiae. 194

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