抗菌胜肽/蛋白質對綠膿桿菌抗菌活性之研究｜國立清華大學博碩士論文庫

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研究生：	林育民 Lin, Yu-Min
論文名稱：	抗菌胜肽/蛋白質對綠膿桿菌抗菌活性之研究 A study in the bactericidal activity of antimicrobial peptide/protein against Pseudomonas aeruginosa
指導教授：	張大慈 Chang, Margaret Dah-Tsyr 廖有地 Liao, You-Di
口試委員:
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 分子與細胞生物研究所 Institute of Molecular and Cellular Biology
論文出版年：	2010
畢業學年度：	98
語文別：	英文
論文頁數：	76
中文關鍵詞：	人類第七號核醣核酸水解酵素、綠膿桿菌、脂蛋白質、抗菌胜肽蛋白質
外文關鍵詞：	human RNase7, P. aeruginosa, Antimicrobial peptides/proteins, outer membrane protein I
相關次數：	點閱：2 下載：0
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Antimicrobial peptides/proteins (AMPs) are widely distributed in nature with vast diversity. Most AMPs share a common feature of an amphipathic structure where clusters of hydrophobic and cationic amino acids are spatially organized into discrete sectors. Ribonucleases (RNases) are abundant in living organisms and play important roles in RNA metabolism, angiogenesis, neurotoxicity, antitumor and antimicrobial activities, among which antimicrobial RNases possess high positively charged residues. To investigate the role of cationic residues of human RNase7 (hRNase7) in its antimicrobial activities against bacteria and yeast, nuclear magnetic resonance (NMR) spectroscopy and site-directed mutagenesis have been carried out. It is found that 22 positively charged residues (18 Lys and 4 Arg) of hRNase 7 exposed to the surface can be classified into three clusters, and the first cluster containing Lys1, Lys3, Lys111, Lys112 located at a flexible coil near the N terminus, rather than the catalytic residues His15, Lys38, and His123 or other two clusters, Lys32, Lys35 and Lys96, Arg97, Lys100, is critical. For most Gram-negative bacteria, the cell surface lipopolysaccharide (LPS) serves as the major target for AMPs. However, the antimicrobial activities of hRNase 7 and α-helical cationic AMPs against P. aeruginosa, a lethal pathogen to immune-compromised hospitalized patients with low antibiotic susceptibility, can be inhibited by the addition of exogenous OprI (outer membrane protein I) or anti-OprI antibody. The modification and internalization of OprI into cytosol triggered by hRNase 7 make bacterial membrane permeable to intracellular components of P. aeruginosa. Our findings highlight a novel mechanism of antimicrobial activity. This is the first report demonstrating a previously unexplored cell surface target of α-helical cationic AMPs rather than LPS, which may be used for screening drugs to treat antibiotic-resistant bacterial infection.

Part 1: Particular Lysine residues of human ribonuclease 7 are critical for membrane permeability and antimicrobial activity………………………………………………..1
1 Introduction    2
1.1 Antimicrobial peptides/proteins diversity    2
1.2 Cationic antimicrobial peptides/proteins in host defence    2
1.3 Presumed bactericidal mechanisms of cationic antimicrobial peptides/proteins    3
1.4 Several members of RNase A superfamily with antimicrobial activities    4
1.5 High positive charge/PI value of hRNase 7 and its antimicrobial activity    5
1.6 Correlation between high positive charge/PI value and antimicrobial activity of hRNase 7    5
2 Materials and Methods    7
2.1 Materials……………………………………………………………………7
2.2 Preparation of recombinant human RNase 7    7
2.3 Enzymatic activity of recombinant hRNase 7    8
2.4 Antibacterial assay    9
2.5 Binding of RNases to bacteria    9
2.6 Assay of bacterial membrane permeability    10
2.7 Nomenclature of mutated hRNase 7 and oligopeptide    10
3 Results    12
3.1 Bactericidal activity of the members of RNase A superfamily    12
3.2 Binding and permeability of RNases in bacterial membrane of P. aeruginosa    12
3.3 Critical residues responsible for bactericidal activity of hRNase 7    13
4 Discussion……………………………………………………………………..15

Part 2: Outer membrane protein I of Pseudomonas aeruginosa is a target of cationic antimicrobial peptide/protein………………………………………………………...27
1 Introduction    28
1.1 Pseudomonas aeruginosa, a lethal pathogen with low antibiotic susceptibility    28
1.2 AMPs, one potential source of novel antibiotics against traditional antibiotic resistant pathogens    28
1.3 AMP’s bactericidal mechanisms remain under debate    29
1.4 Some cell-surface receptors other than LPS may be responsible for         bacterial susceptibility to AMPs.................................................................30
2 Materials and Methods    31
2.1 Materials    31
2.2 Assays of antimicrobial activity and bacterial membrane permeability    31
2.3 Inhibition zone assay of AMPs against bacteria    32
2.4 Binding of AMPs to bacteria    32
2.5 Identification of hRNase 7-binding proteins    33
2.6 Cloning, expression and purification of OprI    33
2.7 Cross-linking assay    34
2.8 Morphological analysis by transmission electron microscopy    35
3 Results    37
3.1 Investigation of LPS roles on the bactericidal activity of AMPs    37
3.2 Identification and production of OprI    38
3.3 rOprI with a polymeric structure    39
3.4 OprI responsible for the susceptibility of P. aeruginosa to □-helical AMPs    39
3.5 Association of OprI with P. aeruginosa surface components    40
3.6 Dissociation of OprI-LPS complex by hRNase 7 in vitro    41
3.7 Direct interaction between OprI and hRNase 7    41
3.8 Modification of OprI by hRNase 7    42
3.9 hRNase 7 induced morphological changes of P. aeruginosa associated with the entry of OprI and hRNase 7    42
4 Discussion    43
Reference    68
Publication list    76

                                

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