本文選題：白念珠菌　切入點：多藥耐藥蛋白　出處：《第二軍醫(yī)大學(xué)》2006年博士論文　論文類型：學(xué)位論文

【摘要】：Cdr1p構(gòu)效關(guān)系的研究有助于深入了解白念珠菌耐藥性產(chǎn)生的分子機(jī)制。采用定點突變方法獲得TMS1(1514L)、TMS2(L563F)、TMS4(W629L和M631I)、TMS6(A772I和L776F)、TMS8(F1239L和M1246Y)和TMS10(A1324L)變異,在釀酒酵母AD1-8u~-菌株中表達(dá),測定表達(dá)變異蛋白菌株藥物敏感性的改變,羅丹明6G外轉(zhuǎn)運功能的改變,及在氮唑類藥物與羅丹明6G共同作用下外轉(zhuǎn)運功能的變化。結(jié)果發(fā)現(xiàn)L776F、M1246Y和A1324L變異引起菌株對氮唑類藥物敏感性明顯增加;1514L、L563F、L776F、F1239L、M1246Y和A1324L變異引起菌株外轉(zhuǎn)運羅丹明6G能力的下降;表達(dá)野生型蛋白菌株中氟康唑、酮康唑、伊曲康唑和咪康唑與羅丹明6G共同作用時抑制羅丹明6G的外轉(zhuǎn)運,而表達(dá)變異蛋白菌株中氮唑類藥物與羅丹明6G共同作用下羅丹明6G的外轉(zhuǎn)運能力各異。本研究首次初步證明TMS4、TMS8和TMS10也是Cdr1p重要的底物結(jié)合轉(zhuǎn)運位點,發(fā)現(xiàn)了與底物結(jié)合轉(zhuǎn)運相關(guān)的關(guān)鍵性氨基酸殘基。
[Abstract]:The study of the structure-activity relationship of Cdr1p is helpful to understand the molecular mechanism of resistance of Candida albicans. By using site-directed mutagenesis method, we obtained the mutagenesis of TMS32011514L, L563FTMS4W629L and M631Ignit6TMI6F1239L and M1246Y), and expressed them in Saccharomyces cerevisiae AD1-8u-, and expressed them in Saccharomyces cerevisiae AD1-8u-. The changes of drug sensitivity and external transport function of Rhodamine 6G were measured. The results showed that the sensitivity of strain L776FU M1246Y and A1324L to azazole increased significantly, and the ability of strain to transport Rhodamine 6G decreased due to the mutation of L776FU M1246Y and A1324L. Fluconazole, ketoconazole, itraconazole and miconazole combined with Rhodamine 6G inhibited the transport of Rhodamine 6G in wild-type protein strains. However, the external transport ability of Rhodamine 6G was different under the interaction of azazole and Rhodamine 6G in the mutant protein expression strain. It was proved for the first time that TMS4TMS 8 and TMS10 were also important substrate-binding transport sites for Cdr1p. Key amino acid residues related to substrate binding transport were found.
【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2006
【分類號】：R379

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本文編號：1628031