Design of Potent, Non-Toxic Antimicrobial Agents Based upon the Structure of the Frog Skin Peptide, Temporin-1CEb from Chinese Brown Frog, Rana chensinensis
Design of Potent, Non-Toxic Antimicrobial Agents Based upon the Structure of the Frog Skin Peptide, Temporin-1CEb from Chinese Brown Frog, Rana chensinensis
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基于中国褐蛙 (Rana chensinensis) 的蛙皮肽 Temporin-1CEb 的结构设计强效、无毒抗菌剂
DOI：
10.1111/j.1747-0285.2012.01363.x
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发表时间：
2012-05-01
影响因子：
3
通讯作者：
Gou, Meng
中科院分区：
文献类型：
--
作者：
Shang, Dejing;Li, Xiaofan;Gou, Meng
Temporin-1CEb对革兰氏阳性菌具有抗菌活性，但其溶血作用限制了其治疗潜力。在本研究中，合成了8个具有改变的阳离子性和疏水性的temporin-1CEb类似物。通过用5个或6个赖氨酸取代α-螺旋亲水面上的中性和非极性氨基酸残基来增加阳离子性和两亲性，可使抗菌效力增加约10倍至40倍，但当正电荷的数目从+6增加至+7时，抗菌效力并未额外增加。用d-赖氨酸取代L-赖氨酸，同时保持净电荷和平均疏水性值，对它的抗菌活性只有微小的影响，而导致它的溶血活性显著下降。在所有的肽中，I-K6具有作为抗微生物剂的最佳潜力，因为其对革兰氏阳性和革兰氏阴性细菌的抗微生物活性是显著的，并且其溶血活性是可忽略的。l-K6采用在50%三氟乙醇/水和30 mM SDS溶液中的α-螺旋。l-K6对大肠杆菌的杀灭率为99.9%。coli和革兰氏阳性菌S.在4x MIC下60 min内对金黄色葡萄球菌的抑菌效果最好，抗菌后效应> 5 h。l-K6影响E. coli和革兰氏阳性菌S.通过快速诱导膜去极化来制备金黄色葡萄球菌质膜。
Temporin-1CEb shows antimicrobial activity against Gram-positive bacteria, but its therapeutic potential is limited by its haemolysis. In this study, eight temporin-1CEb analogues with altered cationicities and hydrophobicities were synthesized. Increasing cationicity and amphipathicity by substituting neutral and non-polar amino acid residues on the hydrophilic face of the alpha-helix by five or six lysines increased antimicrobial potency approximately 10-fold to 40-fold, although when the number of positive charges was increased from +6 to +7, the antimicrobial potency was not additionally enhanced. The substitution of an l-lysine with a d-lysine, meanwhile maintaining the net charge and the mean hydrophobicity values, had only a minor effect on its antimicrobial activity, whereas significantly led a decrease in its haemolytic activity. Of all the peptides, l-K6 has the best potential as an antimicrobial agent because its antimicrobial activity against both Gram-positive and Gram-negative bacteria is substantial, and its haemolytic activity is negligible. l-K6 adopts an alpha-helix in 50% trifluoroethanol/water and 30 mm SDS solutions. l-K6 killed 99.9% of E. coli and S. aureus at 4x MIC in 60 min, and its postantibiotic effect was > 5 h. l-K6 affects the integrity of E. coli and S. aureus plasma membranes by rapidly inducing membrane depolarization.