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研究生:汪靖勛
研究生(外文):WANG, CHING-HSUN
論文名稱:臨床大腸桿菌染色體基因相關粘桿菌素抗藥機轉探討
論文名稱(外文):Chromosomal mechanism of colistin resistance in Escherichia coli of clinical origin
指導教授:林永崇林永崇引用關係
指導教授(外文):LIN, JUNG-CHUNG
口試委員:王志堅林永崇王振泰林邑璁馮長風
口試委員(外文):WANG, SHIH-CHENGLIN, JUNG-CHUNGWANG, JEN-TAYLIN. YI-TSUNGFUNG, CHANG-PHONE
口試日期:2021-11-11
學位類別:博士
校院名稱:國防醫學院
系所名稱:醫學科學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2021
畢業學年度:110
語文別:中文
論文頁數:96
中文關鍵詞:粘桿菌素大腸桿菌抗藥染色體
外文關鍵詞:ColistinE scherichia coliResistancechromosome
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由於在大腸桿菌(Escherichia coli)中質體媒介粘桿菌素(colistin)抗藥基因(mobile colistin resistanc, mcr)造成粘桿菌素抗藥的機轉已有相當的了解,因此我們此研究主要是分別從2個全國多中心微生物抗藥性監測計畫中挑選出缺少mcr基因且對粘桿菌素具有抗藥性的大腸桿菌做進一步的研究。在所有研究菌株中,其中一株粘桿菌素抗藥且不帶有mcr基因的大腸桿菌是從2012年至2015年全國監測計畫裡377株碳青黴烯類抗生素(carbapenem)不敏感大腸桿菌株中(0.2%)挑選出來; 而在另一個2008至2018年的全國監測計畫,則是在7942株的臨床大腸桿菌菌株當中,挑選出11株(0.1%)的粘桿菌素抗藥大腸桿菌。從兩個全國監測計畫中可以發現,粘桿菌素抗藥且不帶有mcr基因的大腸桿菌在整體盛行率是低的。在這些粘桿菌素抗藥的大腸桿菌中,自2012年以來,可以觀察到開始出現具有多重抗藥基因廣效性乙內醯胺酶(extended-spectrum β-lactamases; ESBLs)的序列分型(sequence type, ST) 131和1193粘桿菌素抗藥菌株。針對挑選出來粘桿菌素抗藥的大腸桿菌做進一步研究可以發現,這類型菌株相較於對照組大腸桿菌株MG1655具有較高的pmrHFIJKLM和pmrCAB之基因表現量,針對可能的變異蛋白PmrA和PmrB做進一步研究,發現有數個胺基酸序列變異可能造成粘桿菌素抗藥,其中有三個菌株TSAREC01,TSAREC04和TSAREC41的PmrA中第81位置精胺酸(Arginine, R)被替換為組胺酸(Histidine, H),以及菌株EC3000在PmrB中第6-11位置發生胺基酸缺失突變,在藉由回補實驗後可以證實對粘桿菌素抗藥有顯著影響。而剩下的9株大腸桿菌中,雖在各自的pmrB基因中皆有不同位點變異,但是將這些突變的pmrB基因克隆到pmrB基因剔除的MG1655菌株後,發現這些經轉型作用(transformation)獲得不同突變pmrB基因的MG1655菌株,其粘桿菌素的最小抑菌濃度(minimum inhibitory concentration, MIC)和pmrK基因表現量都沒有變化。顯示這些突變pmrB基因不會造成粘桿菌素抗藥。進一步挑選粘桿菌素抗藥菌株EC3000測試其生長速度與因獲得抗生素抗藥的適應性代價(fitness cost),比起菌株MG1655,菌株EC3000G在生長靜止期(stationary phase)有顯著降低,且在與菌株MG1655的競爭共培養實驗中(competitive co-culture) 也顯示較低的生存優勢。但是將抗藥菌株EC3000培養再不含抗生素培養基中經7天的持續次培養後,仍可以觀察到一部份EC3000菌株持續保有抗藥性。
從我們研究中,我們可以觀察到在台灣不帶有mcr基因粘桿菌素抗藥大腸桿菌,具有在全球廣泛傳播的序列分型ST131和ST1193。同時我們研究也證實在PmrA第81個位置的胺基酸替換(R81H)以及在PmrB第6-11位置的胺基酸缺失突變(Δ6-11, RPISLR)會造成大腸桿菌粘桿菌素抗藥。在PmrB第6-11位置的胺基酸缺失突變(Δ6-11, RPISLR)會影響其生長速率及適應性。但是在不含粘桿菌素環境中仍可以持續存在。未來將針對目前尚未發現抗藥機轉的剩餘菌株利用不同方法包括全基因定序,或轉作子插入定序比對法(Transposon-insertion sequencing methods, TIS)來做進一步研究。

As the colistin resistance due to the mcr-type genes in Escherichia coli were well characterized, mcr-negative colistin resistant E. coli were specifically selected from 2 nationwide surveillance programs in Taiwan for further investigation. From one nationwide surveillance program since 2012 to 2015, one mcr-negative colistin resistant isolate from 377 (0.2%) carbapenem non susceptible E. coli isolates was found. Moreover, a total of 11 mcr-negative colistin resistant isolates of 7942 (0.1%) clinical E. coli were identified from another nationwide surveillance program between 2008 and 2018. Estimated prevalence was low. Identified mcr-negative colistin resistant isolates of ST131 and ST1193 clones with multiple drug resistant phenotypes emerged since 2012. All resistant strains displayed higher expression levels of operon pmrHFIJKLM and pmrCAB compared to the control MG1655 strain. Several amino acid substitutions were identified in PmrA or PmrB. The effects of substitution R81H in PmrA from three strains and in-frame deletion Δ6-11(RPISLR) in PmrB from one strain to colistin resistance were confirmed by complementation experiments. The remaining nine strains harbored several substitutions in PmrB showed neither minimum inhibitory concentration change of colistin nor pmrK expression levels elevation after introducing mutated pmrB alleles to a pmrB-deleted MG1655 indicated that none of the identified mutated pmrB in such strains contributes to colistin resistance. The growth rates of strain EC3000 were lower in the stationary phase comparing with MG1655 and EC3000 revertant. Moreover, growth rates was suppressed in the presence of MG1655 or EC3000 revertant in the competitive co-culture. Nevertheless, there is still a portion of serial passage cultured EC3000 strains without selective pressure for 7 days preserving colistin resistance. In conclusion, the globally spreading clone ST131 and ST1193 among colistin resistant E. coli were observed in Taiwan. The amino acid substitution of R81H in PmrA and in-frame deletion Δ6-11(RPISLR) in PmrB contribute to colistin resistance in E. coli. Although decreased fitness, the persistent colistin resistance of strain EC3000 without selective pressure raised the concern about further spreading. In the future, remaining identified with unknown colistin resistant mechanism would further elucidate using different method including whole genome sequencing or transposon-insertion sequencing methods.
正文目錄 頁
目錄……………………………………………………………………I
表目錄 ……………………………………………………………IV
圖目錄 ……………………………………………………………VI
中文摘要………………………………………………………………VII
英文摘要………………………………………………………………X
第一章 緒言…………………………………………………………1
第一節 粘桿菌素作用及細菌產生粘桿菌素抗藥背景…………1
第二節 粘桿菌素抗藥機轉………………………………………2
第三節 大腸桿菌粘桿菌素抗藥機轉……………………………4
第四節 研究目的…………………………………………………8
第二章 材料與方法…………………………………………………9
第一節 菌株,質體與引子………………………………………9
第二節 酵素,藥劑,套件組,培養基及儀器…………………23
第三節 菌株鑑定及抗生素敏感性測試…………………………26
第四節 CTX-M型乙內醯胺酶基因偵測 ………………………27
第五節 mcr 基因偵測……………………………………………28
第六節 接合試驗…………………………………………………28
第七節 多位點序列分型…………………………………………29
第八節 親緣性分析………………………………………………30
第九節 粘桿菌素抗藥基因定序及分析…………………………31
第十節 pmrA基因剔除菌株製備 ………………………………32
第十一節 pmrB基因剔除菌株製備 ……………………………33
第十二節 野生型pmrB置換大腸桿菌EC3000 revertant置備 35
第十三節 質體基因回補實驗……………………………………36
第十四節 即時聚合酶連鎖反應…………………………………37
第十五節 體外生長曲線測定……………………………………38
第十六節 體外競爭共培養(competition co-culture)……………39
第十七節 大腸桿菌EC3000粘桿菌素抗藥性表徵持久性測定 39
第三章 結果…………………………………………………………41
第一節 粘桿菌素抗藥大腸桿菌特色……………………………41
第二節 粘桿菌素抗藥大腸桿菌相關抗藥基因表現量…………50
第三節 粘桿菌素抗藥大腸桿菌相關抗藥基因結果分析………58
第四節 PmrA胺基酸變異在粘桿菌素抗藥影響…………………62
第五節 PmrB胺基酸變異在粘桿菌素抗藥影響…………………66
第六節 粘桿菌素抗藥大腸桿菌EC3000適應性代價
(fitness cost)測定………………………………………………73
第七節 粘桿菌素抗藥大腸桿菌EC3000抗藥表徵持久性………76
第八節 核苷酸序列登記序號……………………………………76
第四章 討論…………………………………………………………77
第五章 結論…………………………………………………………84
第六章 參考文獻……………………………………………………85
附錄 博士班期間相關發表論文……………………………………96


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