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系統識別號 U0026-1708201617402600
論文名稱(中文) 克雷白氏肺炎桿菌未知碳氫黴烯類抗藥性決定因子之研究
論文名稱(英文) Investigation of the as-yet-unknown carbapenem resistance mechanisms in Klebsiella pneumoniae
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 104
學期 2
出版年 105
研究生(中文) 林喻淳
研究生(英文) Yu-chun Lin
學號 T36034107
學位類別 碩士
語文別 英文
論文頁數 97頁
口試委員 指導教授-顏經洲
共同指導教授-吳俊忠
口試委員-柯文謙
口試委員-鄧景浩
中文關鍵字 克雷白氏肺炎桿菌  碳氫黴烯抗藥性  次世代定序  比較基因體學  單分子即時定序 
英文關鍵字 Klebsiella pneumoniae  carbapenem resistance  next generation sequencing  comparative genomics  Single-molecule real time (SMRT) sequencing 
學科別分類
中文摘要 克雷白氏肺炎桿菌屬於伺機性致病菌,可引起肺炎、泌尿道感染、腦膜炎、肝膿瘍…等感染疾病,在群體感染的情況下,容易導致細菌抗藥性的產生及傳播率大幅提升。碳氫黴烯類藥物為乙內醯胺類藥物家族的一員,是其中最強效、最廣效的藥物,又被稱作〝最後一道防線藥物〞,時常用於治療較嚴重的細菌感染,例如帶有廣效性乙內醯胺酶的菌株感染。由於碳氫黴烯類藥物被廣泛使用,使對其產生抗性的菌株有逐年增加的趨勢,大幅限制用藥的選擇,被視為一嚴重的公衛問題。本研究的目的,在探討克雷白氏肺炎桿菌碳氫黴烯類藥物抗藥性的機轉。在研究中,我們針對同一病人分離得到三基因背景高度相似之菌株,卻對碳氫黴烯類藥物有不同耐受性的臨床菌株進行分析。三菌株帶有相同的乙內醯胺酶,且並未偵測到碳氫黴烯酶活性。在加入排出幫浦抑制劑之後,三菌株對碳氫黴烯類藥物耐受性無顯著變化,顯示對抑制劑敏感之排出幫浦系統應不參與其中。透過萃取外膜蛋白並以SDS-PAGE分析,我們發現三菌株帶有相似的外膜蛋白。分析抗藥性相關之膜通道蛋白基因ompK35和ompK36序列,結果顯示具碳氫黴烯抗性之菌株在OmpK36多了兩個胺基酸。將對碳氫黴烯敏感菌株之OmpK36送入具碳氫黴烯抗性菌株,具碳氫黴烯抗性之菌株對碳氫黴烯類藥物恢復感受性,顯示OmpK36參與碳氫黴烯抗藥性。為了進一步尋找其他可能參與碳氫黴烯抗藥性的作用機轉,我們利用次世代定序 (Next generation sequencing) 與單分子即時定序 (Single-molecule real time sequencing) 試圖解出三株菌株的全基因體。透過重測序 (Resequencing)分析,經由三菌株之基因體兩兩比對,針對專一存在帶有碳氫黴烯抗藥性菌株中的單一核苷酸多型性與小片段核苷酸差異做篩選,找出潛在碳氫黴烯抗藥性決定因子。其中抗碳氫黴烯類藥物之菌株獨有的單一核苷酸多型性與小片段核苷酸,會使得一些基因發生非同義突變 (nonsynonymous mutation),這些突變多發生在轉錄因子,可能和雙组分系统 (Two-component system)和群聚感應 (quorum sensing)相關,進而導致抗藥性產生。
英文摘要 Klebsiella pneumoniae is a Gram-negative pathogen responsible for opportunistic community- and hospital-acquired infections, such as urinary tract infection, pneumonia, meningitis and liver abscess. Infections caused by K. pneumoniae may increase the prevalence of antimicrobial resistance. Since carbapenems (ertapenem, imipenem, and meropenem) are the last-line drugs for treating multi-drug resistant Enterobacteriaceae infections, the emergence of carbapenem resistance has become a serious public health problem, leaving fewer therapeutic options. The objective attempted to identify carbapenem resistance determinants in K. pneumoniae. Three K. pneumoniae isolates from the same patient were analyzed. The three strains had an identical pulsed-field gel electrophoresis pattern, but different susceptibilities to carbapenems. The well-known resistance mechanisms possibly responsible to carbapenem resistance were investigated firstly. The PCR and nucleotide sequencing indicated that they shared the same β-lactamases. The modified Hodge tests and the carbapenem inactivation methods showed the lack of carbapenemases in the three strains. In the presence or absence of efflux pump inhibitors (phenylalanine-arginine β-naphthylamide and carbonyl cyanide 3-chlorophenylhydrazone), no significant difference in susceptibilities to carbapenems of three strains was observed, suggesting that efflux pumps played little role in this regard. The sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis demonstrated that three strains had similar outer membrane profiles. Two major outer membrane porin genes ompK35 and ompK36 were amplified and sequenced. The ompK35 nucleotide sequences were identical, while the ompK36 nucleotide sequence of the non-susceptible isolate had a 2 amino-acid insertion compared to the others. Transformation of ompK36 form the susceptible isolate to the non-susceptible isolate had reversed the susceptibilities to carbapenems, suggesting OmpK36 participation in carbapenem resistance. To search for other possible carbapenem resistance determinants between three highly similar isolates, Illumina-based next generation sequencing and single-molecule real time (SMRT) sequencing were employed. Upon resequencing analysis, these Illumina-based reads were mapped to the single-molecule real time (SMRT) sequencing reads of strain 1756. The SNPs and indels unique in non-susceptible strains and leading to alterations of amino acids were further investigated to understand whether they played roles in carbapenem resistance. Such SNPs and indels were found mostly to be transcriptional regulators associated with two component systems and quorum sensing, suggesting potential participation in carbapenem resistance.
論文目次 中文摘要 i
Abstract iii
Acknoledgement v
Contents vi
List of tables ix
List of figures x
Symbols and Abbreviations xi
1. Introduction 1
1.1 Klebsiella pneumoniae 1
1.2 Antimicrobial agents 1
1.2.1 β-Lactams 1
1.2.2 Fluoroquinolones 1
1.2.3 Aminoglycosides 2
1.2.4 Tetracyclines 2
1.2.5 Rifampins 2
1.2.6 Macrolides 3
1.2.7 Lipopeptides 3
1.3 Antibiotic resistance mechanisms 3
1.4 Resistance to carbapenems in Enterobacteriaceae 4
1.4.1. β-Lactamases 4
1.4.2. Porin loss 6
1.4.3. Efflux pumps 7
1.5 Sequencing platforms 8
1.5.1 Next-generation sequencing 9
1.5.2 Single-molecule real time (SMRT) sequencing 9
1.6 The aims of this study 10
2. Materials and methods 11
2.1 Bacterial strains and plasmids 11
2.2 Bacterial growth condition and storage 11
2.3 Extraction of bacterial DNA 11
2.3.1 Extraction of plasmid DNA 11
2.3.2 Extraction of genomic DNA 11
2.4 Molecular cloning 12
2.4.1 Polymerase chain reaction (PCR) 12
2.4.2 Agarose gel electrophoresis 13
2.4.3 DNA ligation 13
2.4.4 Transformation: heat-shock 13
2.4.5 Transformation: electroporation 14
2.5 Pulse field gel electrophoresis (PFGE) 15
2.6 Antimicrobial susceptibility testing 15
2.6.1 Detection of carbapenemase activity 15
2.6.2 Evaluation of efflux pump activity 17
2.7 β-Lactamase characterization 17
2.8 Analysis of OmpK35 and OmpK36 18
2.9 Extraction of OMPs 18
2.10 Determination of whole-genome sequence by next generation sequencing 19
2.11 Determination of whole-genome sequence by single-molecule real time (SMRT) sequencing 19
2.12 Genome annotation 20
2.13 Genome comparison 20
2.14 Identification of antibiotic resistance related genes 21
3. Results 22
3.1 Antimicrobial susceptibilities to carbapenems 22
3.2 Molecular typing 22
3.3 β-Lactamases characterization 22
3.4 Efflux pump activity 23
3.5 OMP analysis 23
3.6 Genome comparison of strains 1795, 1547, and 1756. 24
3.7 Identification of antibiotic resistance related genes 26
4. Discussion 27
4.1 Antibiotic-resistance in K. pneumoniae 27
4.2 Outer membrane proteins and antibiotic resistance 28
4.3 Efflux pump systems and antibiotic resistance 30
4.4 Carbapenem inactivation method 31
4.5 Performance of sequencing platforms 32
5. Conclusion 34
6. References 35
7. Tables 46
8. Figures 60
9. Appendix 66
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