臺灣博碩士論文加值系統

志賀氏桿菌屬細菌引起的痢疾是一嚴重的大眾健康問題，台灣地區也常有桿菌性痢疾的暴發性流行事件報告。有鑑於細菌抗藥性的問題日益嚴重，多重抗藥性志賀氏菌亦迭有報告，因此本研究探討暴發性及散發性感染的志賀氏菌其抗藥情形與抗藥基因，另外亦探討integron、抗藥性質體及其在散佈抗藥基因所扮演的角色。
本研究之實驗菌株包括1993至1998年所收集的數次暴發性感染分離之Shigella sonnei菌株，以及1982至1987年間所收集的32株散發性S. sonnei和31株散發性S. flexneri菌株。抗生素感受性試驗結果發現菌株對ampicillin、chloramphenicol、streptomycin、sulfisoxazole、tetracycline及trimethoprim的抗藥性較為普遍，除了5株散發性菌株外，其餘菌株呈多重抗藥性。以PCR、核酸定序及限制酶分析得知class 1 integron所攜帶的基因片匣主要是抗藥性基因，包括trimethoprim（dfr12、17）、streptomycin（aadA1、2、5）、ampicillin（oxa30）、chloramphenicol（cmlA1）與streptothricin（sat）等藥物之抗藥基因片匣，而class 2 integron則均攜帶dfrIa、sat與aadA1之基因片匣組合。至於位在integron外的抗藥基因則是發現包括ampicillin（blaTEM）、chloramphenicol（cat1）、sulfisoxazole（sul2）和tetracycline（tetA、tetB、tetC）之抗藥基因。
南方雜交反應結果發現不同大小的抗藥性質體存在，菌株攜帶的的class 1 integron及抗藥基因如blaTEM、cat1、 tetB與tetC多位在分子量95〜148 kb的質體上，其中以130 kb的質體最普遍，而tetA 與sul2則多位於8.5或6 kb的質體上，至於class 2 integron並未存在於質體上。接合試驗結果發現部份抗藥性質體具轉移性，可一併散佈質體所攜帶的抗藥基因與class 1 integron。此外，菌株所帶的抗藥基因及class 1 integron位在同一個質體上，可能造成co-selection的情形，使得抗藥性質體被篩選出來，而保留了細菌的多重抗藥性。

Shigella spp. infections have been recognized as a major cause of diarrheal disease and become a serious public health issue in Taiwan. The resistance to most of the highly used antimicrobials in Shigella spp. has drawn growing concerns in recent years as increasing infections caused by multi-resistant Shigella were widely reported. Therefore, this research was to study the antimicrobial resistance and antimicrobial resistance genes of Shigella strains of outbreak and sporadic infections. Characteristics of integrons and plasmids were also studied to further ascertain their roles in dissemination of antimicrobial resistance genes.
Shigella strains analysed in this study were isolated from outbreak and sporadic infections. Outbreak isolates of Shigella sonnei were isolated during 1993 to 1998. Sporadic strains included 32 S. sonnei and 31 S. flexneri isolates collected between 1982 and 1987. Antimicrobial susceptibility testing showed that resistance to ampicillin, chloramphenicol, streptomycin, sulfisoxazole, tetracycline and trimethoprim was found frequently among Shigella strains. All of the strains were even multi-resistant except for 5 sporadic isolates. According to PCR, DNA sequencing and restriction enzyme analysis, the gene cassettes contained in class 1 integrons included those encoding resistance to trimethoprim (dfr12 and dfr 17), streptomycin (aadA1, aadA2, and aadA5), ampicillin (oxa30), chloramphenicol (cmlA1) and streptothricin (sat). Meanwhile, all class 2 integrons carried the same three cassettes, dfrIa, sat and aadA1. Other antimicrobial resistance genes not associated with integrons, on the other hand, conferred resistant to ampicillin (blaTEM), chloramphenicol (cat1), sulfonamide (sul2) and tetracycline (tetA, tetB and tetC).
Results from Southern hybridization pointed out there existed plasmids of different sizes. Most of the resistance genes such as blaTEM, cat1, tetB and tetC as well as the genes associated with class 1 integrons were located on the plasmids ranging from 95 to 148 kb, among which the plasmids of 130 kb were the most prevalent. TetA and sul2 were mainly located on the plasmids of 8.5 or 6 kb. Class 2 integrons were absent on plasmids. In addition, conjugation experiments revealed that some plasmids were transferable, accompanied with the resistance genes and class 1 integrons they carried. Furthermore, co-selection effect resulting from the co-existence of most resistance genes and class 1 integrons on the same plasmid may lead to plasmids being selected, thus facilitating the persistence of multi-resistance in bacteria.

中文摘要1
英文摘要3
緒論5
（一）研究背景5
（二）研究目的13
材料與方法14
（一）實驗菌株之收集14
（二）藥物感受性試驗15
（三）Class 1 integron之偵測16
1. 模板DNA之製備17
2. 聚合酶鏈鎖反應17
3. 瓊脂醣明膠電泳18
（四）Class 1 integron基因片匣的分析19
1. 聚合酶鏈鎖反應20
2. PCR產物的純化21
3. 核酸自動定序分析22
4. 基因序列的電腦分析22
（a）基因序列相似性比對22
（b）限制酶切割位置分析23
5. 限制酶切割試驗23
6. Conserved segment PCR（CS-PCR） 24
陰性的integron基因片匣分析
（五）Class 2 integron的偵測及其所帶之基因片匣分析26
（六）菌株之抗藥基因分析27
（七）Class 1、2 integron及抗藥基因於菌株內存在位置之分析28
1. 質體DNA之抽取28
2. 瓊脂醣明膠電泳29
3. 南方雜交分析29
目錄
（a）DNA的轉印29
（b）以PCR增幅製備探針31
（c）前雜交32
（d）雜交32
（e）雜交後清洗33
（f）偵測以DIG標記之已雜交探針33
（g）自動放射顯影35
（八）抗藥性轉移之分析—接合試驗（conjugation） 35
結果37
（一）Shigella spp.抗藥情形37
（二）Class 1 integron於菌株內存在情形38
（三）Class 1 integron攜帶之基因片匣38
（四）Class 2 integron於菌株內存在情形與攜帶之基因片匣41
（五）Integron攜帶之抗藥基因片匣與菌株抗藥性之相關性42
（六）Shigella spp.位在integron外之抗藥基因42
（七）抗藥性質體之分析44
（八）Shigella spp.抗藥性質體與抗藥性轉移情形46
討論49
（一）Shigella spp.抗藥情形49
（二）Integron存在情形及攜帶的基因片匣49
（三）Shigella spp.所攜帶的抗藥基因53
（四）Shigella spp.的抗藥性質體56
（五）結論58
圖60
表71
附圖78
參考文獻80

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