Contribution of Each Amino Acid Residue in Polymyxin B3 to Antimicrobial and Lipopolysaccharide Binding Activity
Contribution of Each Amino Acid Residue in Polymyxin B3 to Antimicrobial and Lipopolysaccharide Binding Activity
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DOI：
10.1248/cpb.57.240
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发表时间：
2009-03-01
影响因子：
1.7
通讯作者：
Sakura, Naoki
中科院分区：
文献类型：
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作者：
Kanazawa, Kazushi;Sato, Yuki;Sakura, Naoki
本研究利用16个合成的多粘菌素B-3类似物，包括丙氨酸扫描类似物，对多粘菌素B-3的构效关系进行了研究，以阐明其侧链对抗菌活性和脂多糖（LPS）结合的贡献。在这些类似物中，[Ala(5)]-polymyxin B-3对大肠杆菌（E. coli）、鼠伤寒沙门氏菌（S. Typhimurium）和铜绿假单胞菌（P. aerughtosa）的抑菌活性显著降低，MIC值为4-16 nmol/ml，表明位于第5位的Dab （α， γ -二氨基丁酸）残基是最重要的抑菌残基。Dab位于内酰胺环内（位置5、8和9）的抑菌作用大于位于环外（位置1和3）的抑菌作用。[D-Ala(6)]-、[L-Phe(6)]-、[Ala(7)]-和[Gly(7)]-多粘菌素B的类似物保留了有效的抑菌活性，这表明D-Phe(6) - leu(7)区域疏水特性的降低和位置6的d构型对抗菌活性都不是必不可少的。LPS结合研究表明，内酰胺环疏水性降低影响不大，但Dab 1、3、5、8、9位残基的n -氨基功能对LIPS结合影响较大，其中Dab的贡献最为显著。
This study on the structure-activity relationship of polymyxin B, a cyclic peptide antibiotic, used sixteen synthetic polymyxin B-3 analogs including alanine scanning analogs to elucidate the contribution of the side chains to antimicrobial activity and lipopolysaccharide (LPS) binding. Of these analogs, [Ala(5)]-polymyxin B-3 showed greatly reduced antimicrobial activity against Escherichia coli (E. coli), Salmonella Typhimurium (S. Typhimurium) and Pseudomonas aeruginosa (P. aerughtosa) with MIC values of 4-16 nmol/ml, suggesting that the Dab (alpha,gamma-diaminobutyric acid) residue at position 5 is the most important residue contributing to bactericidal activity. The antibacterial contribution of Dab when located within the lactam ring (positions 5, 8 and 9) was greater than when located outside the ring (positions 1 and 3). [D-Ala(6)]-, [L-Phe(6)]-, [Ala(7)]-, and [Gly(7)]-polymyxin B, analogs retained potent antimicrobial activity, indicating that neither the reduction of hydrophobic character of the D-Phe(6) -Leu(7) region nor the D-configuration at position 6 is indispensable for antimicrobial activity. LPS binding studies showed that decreased hydrophobicity of the lactam ring had little effect, but the N-gamma-amino function of the Dab residues at position 1, 3, 5, 8 and 9 greatly affected LIPS binding, with the contribution of Dabs being the most significant.