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研究生:李冠德
論文名稱:霍亂弧菌多重藥物ABC轉運蛋白VcaM聚合型態與其作用基質探討
論文名稱(外文):Investigating the oligomeric state and the drug substrate of multidrug ABC transporter VcaM from Vibrio cholerae
指導教授:林泓廷
指導教授(外文):Hong-Ting Lin
學位類別:碩士
校院名稱:國立臺灣海洋大學
系所名稱:食品科學系
學門:農業科學學門
學類:食品科學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:中文
論文頁數:80
中文關鍵詞:霍亂霍亂弧菌ABC轉運蛋白多重抗藥性VcaM
外文關鍵詞:CholeraVibrio choleraABC transportermultidrug resistanceVcaM
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霍亂 (Cholera) 流行在50多個國家中,所引起的急性腹瀉,造成快速的水份、電解質流失,每年造成12萬人的死亡。霍亂是由霍亂弧菌 (Vibrio cholerae) 血清型O1或O139所引起的,臨床上治療中液體的補充是最為重要,為了減少發病時間、減緩病情並防止傳染,多使用norfloxacin、tetracycline或fluoroquinolone等幾類抗生素進行治療,隨著抗藥性的出現,治療霍亂的成功率也逐漸下降。本論文旨在探討霍亂弧菌中的多重藥物ABC轉運蛋白VcaM的特性,希望對於解決微生物日益增加的抗藥性有所幫助。含vcaM基因之質體的E. coli C43 (DE3) 菌株,經由誘導表現蛋白質,利用Triton X-100將VcaM蛋白質自細胞膜溶出,並以親和性管柱進行一次純化,膠體層析管柱進行二次純化獲得純化的VcaM蛋白,每公升E. coli培養液約可純化出1 mg VcaM。純化過的蛋白質以蛋白質電泳確認分子量介於55 kDa與72 kDa之間,與VcaM (68.7 kDa) 相同,且經Western blot確認。純化的VcaM蛋白ATPase活性可用孔雀綠呈色分析法得知,經由一次純化的VcaM蛋白之Vmax為57.79 nmole Pi/mg VcaM/min、Km為851.95 μM,計算kcat為0.066 S-1;經由二次純化的VcaM雙聚體的ATPase活性測定顯示Vmax為32.33 nmole Pi/mg VcaM/min、Km為529.99 μM,並計算kcat為0.037 S-1;而在二次純化的高聚合度的VcaM部分則是不具有ATPase活性。在in vivo試驗中,會以E. coli藥物敏感菌株Kam3 (DE3),使其表現VcaM於細胞膜上,進行半抑制濃度 (half-inhibitory concentration) 試驗。結果顯示表現VcaM可以提高E. coli Kam3抗性對於macrolide類的erythromycin 達60 μg/ml、clarithromycin 32 μg/ml、azithromycin 8 μg/ml,分別相較於E. coli Kam3位表現VcaM的控制組,提高了16倍、16倍及4倍,顯示VcaM屬於轉運Macrolide類藥物的轉運蛋白;另外VcaM也可提供染劑rhodamin 6G抗性達128μg/ml,2倍高於控制組。VcaM以SEC與酚硫酸法探討其聚體型態。SEC結果發現detergent-solubilized VcaM在二次純化中有兩個peaks,顯示不只一種聚合型態。綜合SEC與酚硫酸結果,推測VcaM在二次純化中有為二聚體及不規則聚體兩種聚合形態。
Epidemic cholera spreads more than 50 countries, and causes rapid loss of fluid and electrolytes that could lead to profound dehydration, circulatory collapse, and death. Cholera kills 120 thousand people each year. Cholera is caused by toxigenic strains of Vibrio cholerae serogroups O1 and O139. In clinic, liquid supplement is the most important treatment, and antibiotics are used as part of treatment for cholera to shorten the duration of diarrhea and forestall spread of the organism. Norfloxacin, tetracycline and fluoroquinolones are commonly used for the treatment of cholera. Since antibiotic-resistant Vibrio cholerae have been reported, cholera treatment success rate has gradually decreased. This thesis aimed to characterize the multidrug ABC transporter VcaM from V. cholera, and it will be beneficial to combat the increasing drug resistance. E. coli C43 (DE3) harboring the plasmid encoding VcaM protein was induced and the VcaM protein was overexpressed. Detergent Triton X-100 was used to extract VcaM from the cell membrane, and the purification of VcaM was accomplished by using affinity and gel filtration chromatography. The yield of VcaM was approximately 1 mg/L cell culture. SDS-PAGE showed that a band of putative VcaM was located between 55 kDa and 72 kDa. This size is consistent with estimated VcaM molecular weight (68.7 kDa) and later confirmed by western blot. The ATPase activity of detergent-solubilized VcaM was detected by Malachite green assay. The ATPase activity of purified VcaM from affinity chromatography gave a Vmax of 57.79 nmole Pi/mg VcaM/min, a Km of 851.95 μM, and a kcat of 0.066 S-1; the dimeric VcaM from gel filtration showed a Vmax of 32.33 nmole Pi/mg VcaM/min, a Km of 529.99 μM, and a kcat is 0.037 S-1. Nevertheless, the higher oligomeric VcaM from gel filtration chromatography did not have ATPase activity. In vivo, E. coli Kam3 (DE3) harboring the plasmid encoding VcaM protein was used in the half-inhibitory concentration (IC50) test. The result showed that overexpression of VcaM could elevate the IC50 of E. coli Kam3 to macrolides erythromycin (more than 60 μg/ml), clarithromycin (32 μg/ml) and azithromycin (8 μg/ml), which were, respectively, 16-fold, 16-fold, and 4-fold higher than that of control. This result indicated that VcaM is a transporter of macrolide. In addition, VcaM could increase the MIC50 to rhodamin 6G of 128 μg/ml, which is 2-fold higher than the control. Investigating on VcaM oligomeric state by using size exclusion chomatography (SEC) and phenol-sulfuric acid colorimetric assay. Our data indicated that the oligomeric states of detergent-solubilized VcaM were dimer and irregular oligomers.
摘要 IV
Abstract V
目錄 VI
圖目錄 VIII
表目錄 IX
附錄目錄 X
縮寫表 XI
壹、前言 1
貳、文獻回顧 2
一、抗生素 2
1.1 抗生素起源 2
1.2 抗生素種類及作用機制 2
1.3 抗生素使用規範 3
二、多重抗藥性 4
2.1 多重抗藥性來源途徑 4
2.2 抗生素與多重抗藥性關係 4
2.3 多重抗藥性作用機制 5
三、藥物轉運蛋白 7
3.1 轉運蛋白分類 7
3.2 ABC轉運蛋白 8
3.2.1 ABC轉運蛋白結構 8
3.2.2 ABC轉運蛋白轉運機制 9
3.2.3 ABC轉運蛋白的研究發現 9
四、霍亂弧菌 11
4.1 霍亂弧菌中的多重抗藥性來源 11
4.2 霍亂弧菌與疾病 12
4.3 霍亂弧菌中的ABC轉運蛋白VcaM 13
参、實驗設計 14
肆、實驗材料與方法 15
一、實驗材料 15
1. 載體與菌株 15
1.1 vcaM基因來源 15
1.2 菌株及載體 15
1.3 Primers 15
2. 培養基與抗菌藥物 15
2.1 培養基 15
2.2 抗生素 16
2.3 其他抑菌物質 16
3. 試劑組與化學藥品 16
3.1 試劑組 16
3.2 化學藥品 17
4. 酵素與抗體 17
5. 實驗儀器 17
二、實驗方法 19
1. 建構VcaM表現載體 19
1.1 聚合酶連鎖反應 19
1.2 DNA電泳及純化 19
1.3 限制酶剪切及DNA黏合 20
1.4 質體轉型 21
2. 蛋白質表現與純化 21
2.1 蛋白質表現 21
2.2 蛋白質純化 21
3. 蛋白質一般特性分析 22
3.1 蛋白質電泳 22
3.2 蛋白質濃度測定 23
3.3 Western blot 23
4. ATP酶活性測試 24
5. VcaM轉運基質鑑定 25
6. VcaM在detergent中的oligomeric state確立 26
6.1 Size exclusion chromatography 26
6.2 Phenol-sulfuric acid colorimetric assay 26
伍、結果與討論 28
一、VcaM基因cloning 28
1.1 聚合酶鏈鎖反應擴增vcaM基因 28
1.2 重組質體檢測 28
二、VcaM蛋白質表現與純化 29
2.1 金屬親和性純化 29
2.2 Size exclusion chromatography 29
三、VcaM蛋白質一般特性分析 30
3.1 蛋白質電泳 30
3.2 蛋白質濃度測定 30
3.3 Western blot 30
四、VcaM蛋白質活性分析 32
五、VcaM轉運基質鑑定 34
六、VcaM在detergent中的oligomeric state確立 36
6.1 Size exclusion chromatography 36
6.2 Phenol-sulfuric acid colorimetric assay 36
結論 38
陸、參考文獻 39

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