抗生素已廣泛應用在各種感染疾病的治療及預防，然而基於天擇，致病細菌為求存活逐步演為化具有抗藥性的突變株，使其在有抗生素存在的環境中持續大量繁殖。抗微生物胜肽廣泛存在於自然界中，為抵抗外來病原菌的先天免疫分子，其應用及研究有助於發展非抗生素類的抗病原體用藥。針對目前對抗生素產生抗藥性的細菌發展新型醫療用藥，已解決今日抗生素濫用而導致的病症及隱憂。由台灣品種鱟(Taiwanese Tachypleus tridentatus)血漿中分離之血漿凝集素具有辨識革蘭氏陽性、陰性菌以及其他病源菌表面分子型態(Pathogen-associated molecular pattern，PAMP)的能力。本實驗室成功使用大腸桿菌系統表現與純化重組鱟血漿凝集素(recombinant horseshoe crab plasma lectin，rHPL)，除了具有細菌之脂多醣內毒素辨識活性外，亦可專一結合細菌表面特殊的鼠李糖 (rhamnose)。由於rHPL的結構資訊尚未明瞭，本研究首先以Phyre2網站預測其結構，再以‘附加特徵排比’方法推測五個可能參與配體結合的親水性芳香環胺基酸(酪胺酸88、色胺酸91、苯丙胺酸143、苯丙胺酸145、色胺酸147)。再將此預測的五個胺基酸單點突變為丙胺酸，進一步以酵素免疫分析法測試突變株與配體的結合能力。本研究結果顯示當酪胺酸88或苯丙胺酸145突變時，突變株與細菌及配體的結合能力大幅下降約百分之八十，證實酪胺酸88與苯丙胺酸145為重要的配體結合位。此外，本研究證實rHPL具有抑制綠膿桿菌以及李斯特菌生長的能力，並發現rHPL突變株失去抑菌能力，進一步證實rHPL需透過結合病源菌表面的醣類以達到抑菌效果。本論文利用生物資訊之預測探討rHPL結構、功能與機制之間的關聯性，有助於發展新穎致病菌檢測及抗菌劑等生醫應用。

Rapid emergence of antibiotic-resistant strains of pathogens, together with sluggish discovery of new antibacterial agents has led to the need to find alternative treatments. Antimicrobial peptides (AMPs), or host defense proteina, are essential components of innate immune systems. The AMP field is growing rapidly in response to the demand for novel antimicrobial agents against drug-resistant pathogens. Recombinant horseshoe crab plasma lectin (rHPL) derived from hemolymph of Taiwanese Tachypleus tridentatus has been successfully expressed and purified in Escherichia coli system in our laboratory, and it recognizes a specific monosaccharide on lipopolysaccharide, rhamnose, on bacterial surface. Since neither secondary nor tertiary structure of rHPL has ever been solved yet, Phyre2 database was applied to predict in silico rHPL structure, and the resullt showed that rHPL might contain two putative functional domains, nHPLNTD and nHPLCTD. As aromatic residues surrounded by polar residues within two amino acids in neighboring sequences, namely “hydrophilic aromatic residues” (HARs), are reported to involve in glycan ligand binding, sequence analysis revealed that 5 HARs (Y88, W91, F143, F145, and W147) in rHPL might possibly served as ligand binding sites. Interestingly, mutants of Y88A located in nHPLNTD and F145A located in nHPLCTD lost approximately 80% pathogen and LPS binding activities, strongly suggesting that these 2 HARs were crucial for in vitro bacteria and LPS binding. In addition, wildtype rHPL was shown to inhibit growth of Pseudomonas aeruginosa PAO1 and Listeria monocytogenes in a concentration-dependent manner. Whereas, rHPL(Y88A) and rHPL(F145A) with minor differences in secondary structures lost growth inhibitory activity to the bacteria, indicating that rHPL inhibited bacterial growth through molecular interaction with key ligand binding residues Tyr88 and Phe145. Structure-function correlation between rHPL and glycan ligand may further facilitate development of novel diagnostic and therapeutic strategies for microbial pathogens.

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