Radzishevsky Inna S, Rotem Shahar, Zaknoon Fadia, Gaidukov Leonid, Dagan Arie, Mor Amram
Laboratory of Antimicrobial Investigation, Department of Biotechnology & Food Engineering, Technion-Israel Institute of Technology, Haifa, Israel.
Antimicrob Agents Chemother. 2005 Jun;49(6):2412-20. doi: 10.1128/AAC.49.6.2412-2420.2005.
To investigate the importance of increased hydrophobicity at the amino end of antimicrobial peptides, a dermaseptin derivative was used as a template for a systematic acylation study. Through a gradual increase of the acyl moiety chain length, hydrophobicity was monitored and further modulated by acyl conversion to aminoacyl. The chain lengths of the acyl derivatives correlated with a gradual increase in the peptide's global hydrophobicity and stabilization of its helical structure. The effect on cytolytic properties, however, fluctuated for different cells. Whereas acylation gradually enhanced hemolysis of human red blood cells and antiprotozoan activity against Leishmania major, bacteria displayed a more complex behavior. The gram-positive organism Staphylococcus aureus was most sensitive to intermediate acyl chains, while longer acyls gradually led to a total loss of activity. All acyl derivatives were detrimental to activity against Escherichia coli, namely, but not solely, because of peptide aggregation. Although aminoacyl derivatives behaved essentially similarly to the nonaminated acyls, they displayed reduced hydrophobicity, and consequently, the long-chain acyls enhanced activity against all microorganisms (e.g., by up to 12-fold for the aminolauryl derivative) but were significantly less hemolytic than their acyl counterparts. Acylation also enhanced bactericidal kinetics and peptide resistance to plasma proteases. The similarities and differences upon acylation of MSI-78 and LL37 are presented and discussed. Overall, the data suggest an approach that can be used to enhance the potencies of acylated short antimicrobial peptides by preventing hydrophobic interactions that lead to self-assembly in solution and, thus, to inefficacy against cell wall-containing target cells.
为了研究抗菌肽氨基末端疏水性增加的重要性，一种皮肤素衍生物被用作系统酰化研究的模板。通过逐渐增加酰基部分的链长，监测疏水性，并通过将酰基转化为氨酰基进一步调节疏水性。酰基衍生物的链长与肽的整体疏水性逐渐增加及其螺旋结构的稳定性相关。然而，对不同细胞的溶细胞特性的影响有所波动。酰化逐渐增强了人红细胞的溶血作用以及对杜氏利什曼原虫的抗寄生虫活性，而细菌表现出更复杂的行为。革兰氏阳性菌金黄色葡萄球菌对中间酰基链最敏感，而较长的酰基逐渐导致活性完全丧失。所有酰基衍生物对大肠杆菌的活性均有损害，这主要是由于肽聚集，但并非唯一原因。尽管氨酰基衍生物的行为与未胺化的酰基基本相似，但它们的疏水性降低，因此，长链酰基增强了对所有微生物的活性（例如，氨月桂酰衍生物的活性提高了12倍），但其溶血活性明显低于相应的酰基衍生物。酰化还增强了杀菌动力学和肽对血浆蛋白酶的抗性。文中展示并讨论了MSI-78和LL37酰化后的异同。总体而言，这些数据表明了一种方法，可通过防止导致溶液中自组装从而对含细胞壁靶细胞无效的疏水相互作用，来提高酰化短抗菌肽的效力。
