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系統識別號 U0026-2207201009523200
論文名稱(中文) 以探針雜合反應法檢測結核桿菌群之抗藥性
論文名稱(英文) Detection of Antibiotic Resistance in Mycobacterium tuberculosis Complex by Probe Hybridization
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系碩博士班
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 98
學期 2
出版年 99
研究生(中文) 黃新惠
研究生(英文) Hsin-Hui Huang
學號 t3697107
學位類別 碩士
語文別 中文
論文頁數 127頁
口試委員 指導教授-張長泉
口試委員-吳俊忠
口試委員-周如文
口試委員-盧柏樑
口試委員-薛博仁
中文關鍵字 結核菌群  抗藥性  寡核苷酸晶片 
英文關鍵字 Mycobacterium tuberculosis complex  antibiotic resistance  oligonucleotide array 
學科別分類
中文摘要 結核病(tuberculosis)是由結核菌群(Mycobacterium tuberculosis complex, MTBC)所引起,在2008年全球有920萬結核病新病例,造成130萬人死亡,且過去十年來結核菌群的抗藥性日益增加。結核菌群的抗藥性與數個基因發生點突變(point mutation)有關,rifampin (RIF), isoniazid (INH), ethambutol (EMB), streptomycin (SM), 及fluoroquinolones (FQs)的抗藥性分別與rpoB, katG及mabA上游基因, embB, rpsL和rrs, 及gyrA突變有關。傳統的比例法(proportional method)藥物感受性詴驗需三週時間。本研究欲發展寡核苷酸晶片(oligonucleotide array),檢測抗藥性相關基因的突變,以預測MTBC對上述抗生素之感受性。從rpoB (codons 511, 513, 516, 522, 526, 531與533), katG (codon 315), upstream of mabA (nucleotides -8與-15), embB (codons 306, 319與406), rpsL (codons 43與88), rrs (nucleotides 513與516)以及gyrA (codons 90, 91與94)基因,設計完全配對(complete match)和不完全配對(mismatch)的寡核苷酸探針。利用多套式PCR (multiplex PCR)將上述基因同時放大,再把標記毛地黃素(digoxigenin)之PCR產物與尼龍膜上之探針雜合反應,以肉眼或軟體(Image Quant TL software, GE Healthcare, Piscataway, NJ)比較成對探針的反應訊號強弱,以檢測是否有點突變。本研究測詴了195株已知藥物感受性的MTBC細菌,晶片的靈敏度(sensitivity)為RIF (97.9%), INH (88.2%), EMB (50%), SM (51.4%)與FQs (81.3%),特異性(specificity)為RIF (95.7%), INH (96.5%), EMB (100%), SM (100%)與FQs (100%)。晶片之陽性預測值(positive predictive value)分別為RIF (88.7%)、INH (93.8%)、EMB (100%)、SM (100%)及FQs (100%),而陰性預測值(negative predictive value)分別為RIF (99.3%)、INH (93.2%)、EMB (82.6%)、SM (73.7%)及FQs (97.7%)。本研究可以快速預測MTBC菌株對以上五種抗生素之抗藥性,也有潛力可用於檢測Mycobacteria Growth Indicator Tube (MGIT, Becton Dickinson Microbiology Systems, Sparks, MD, USA)陽性培養中MTBC之抗藥性。本研究有些探針的反應較弱,需要進一步改善,整個反應時間約為8小時。
英文摘要 Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis complex (MTBC). In the world, there were 9.2 million new cases and 1.3 million people died from TB in 2008. In the passed decades, antibiotic resistance in MTBC is a serious problem worldwide. Antibiotic resistance is associated with point mutations in several genes in MTBC, including rpoB for rifampin (RIF), katG and the mabA promoter for isoniazid (INH), embB for ethambutol (EMB), rpsL and rrs for streptomycin (STR), and gyrA for fluoroquinolone (FQs) resistance. The purpose of this study was to develop an oligonucleotide array to rapidly detect the point mutations in these genes conferring drug resistance to MTBC.
Specific oligonucleotide probes were designed to detect mutations in rpoB (codons 511, 513, 516, 522, 526, 531, and 533), katG (codon 315), the upstream of mabA (positions -8 and -15), embB (codons 306, 319, and 406), rpsL (codons 43 and 88), rrs (positions 513 and 516), and gyrA (codons 90, 91, and 94). The method consisted of multiplex PCR amplification of these genes, followed by hybridization of the digoxigenin-labeled PCR products to oligonucleotide probes immobilized on nylon membrane. The hybridization signal could be observed by the naked eye or by using the Image Quant TL software (GE Healthcare, Piscataway, NJ, USA). A total of 195 clinical MTBC isolates with known drug susceptibility patterns were tested in this study. The sensitivities of the array were 97.9 (RIF), 88.2 (INH), 50 (EMB), 51.4 (SM), and 81.3% (FQs), respectively. The specificities of the array were 95.7 (RIF), 96.5 (INH), 100 (EMB), 100 (SM), and 100% (FQs), respectively. The positive predictive values of the array were 88.7 (RIF), 93.8 (INH), 100 (EMB), 100 (SM), and 100% (FQs), respectively, while the negative predictive values were 99.3 (RIF), 93.2 (INH), 82.6 (EMB), 73.7 (SM), and 97.7% (FQs), respectively. The whole procedures of array hybridization took approximately 8 h. Furthermore, preliminary test revealed that direct detection of antibiotic resistance in positive Mycobacteria Growth Indicator Tube (MGIT, Becton Dickinson Microbiology Systems, Sparks, MD, USA) cultures containing MTBC was possible. In conclusion, the array can effectively detect point mutations in genes associated with antibiotic resistance in MTBC isolates. However, some probes need to be modified to increase the hybridization signals.
論文目次 中文摘要 ............................................................................................ I
Abstract ...........................................................................................III
致謝................................................................................................... V
目錄.................................................................................................. VI
表目錄 .............................................................................................. X
圖目錄 ........................................................................................... XII
緒論.................................................................................................... 1
結核菌群 (Mycobacterium tuberculosis complex, MTBC) ......................... 1
結核菌之流行病學 .............................................................................. 1
結核病治療 .......................................................................................... 3
實驗室診斷 (Laboratory diagnosis) ............................................................. 4
抗藥性結核菌分子生物學 ............................................................................ 5
分子生物學之鑑定方法 ...................................................................... 8
研究目的 .............................................................................................. 9
研究架構 ............................................................................................ 10
材料與方法 ..................................................................................... 11
參考菌株(reference strains) ............................................................... 11
臨床結核菌群(MTBC)菌株DNA .............................................................. 11
DNA萃取 (DNA extraction) ...................................................................... 12
建構internal amplification control DNA .................................................... 13
抗藥性基因之增幅及定序 .......................................................................... 14
多重聚合酶鏈反應(Multiplex PCR) ........................................................... 15
分子選殖(Molecular cloning) ...................................................................... 15
質體DNA萃取 ................................................................................. 17
以定點突變(site-directed mutation)建構含特定單一核苷酸變異(SNP)之DNA片段 .................................................................................................... 19
特異性探針 (specific probes) 之設計 ....................................................... 20
結核菌群抗藥性晶片製備 .......................................................................... 23
晶片雜合反應 (chip hybridization) ............................................................ 24
晶片雜合反應之結果判讀 .......................................................................... 25
靈敏度(sensitivity)、特異性(specificity)、陽性預測值(positive predictive value, PPV)、及陰性預測值(negative predictive value, NPV)之定義 ..... 27
結果.................................................................................................. 29
抗藥性基因之增幅 ............................................................................ 29
定點突變之DNA建構 ............................................................................... 29
探針篩選 ............................................................................................ 29
結核菌群正對照組 (Mycobacterium tuberculosis complex positive control) 探針 .............................................................................................................. 30
臨床結核菌群(MTBC)菌株抗藥性偵測 .................................................... 30
抗藥基因定序 .................................................................................... 32
多重聚合酶鏈反應(Multiplex PCR) ........................................................... 32
以多重聚合酶鏈反應檢測臨床結核菌群(MTBC)抗藥性 ....................... 33
MGIT陽性臨床檢體之結核菌群抗藥性偵測 .......................................... 33
非結核分枝桿菌(nontuberculous mycobacteria, NTM)之晶片測詴 ......... 34
簡化型抗藥性晶片之驗證(validation) ....................................................... 35
以簡化型晶片測詴臨床菌株抗藥性 .......................................................... 35
以多重聚合酶鏈反應(multiplex PCR)進行簡化抗藥性晶片之測詴 ....... 36
晶片靈敏度(sensitivity)與特異性(specificity) ........................................... 36
陽性預測值(positive predictive value, PPV)與陰性預測值(negative predictive value, NPV) ................................................................................. 37
討論.................................................................................................. 39
晶片結果與傳統藥敏性詴驗結果不一致之菌株...................................... 39
某突變codon對鄰近codon探針反應之影響 .......................................... 40
晶片對結核菌群異質性抗藥性(heteroresistance)之檢測 ......................... 41
多套式聚合酶鏈反應(Multiplex PCR) ....................................................... 41
非結核分枝桿菌與探針交叉反應 .............................................................. 42
簡化之抗藥性晶片 ............................................................................ 42
抗藥性晶片與商業化套組之比較 .............................................................. 43
抗藥性晶片與定序結果之比較 .................................................................. 43
結論.................................................................................................. 46
參考文獻 ......................................................................................... 47
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