Department of Biomolecular Systems and ‡Department of Interfaces, Research Campus Golm, Max Planck Institute of Colloids and Interfaces , 14424 Potsdam, Germany.
Biomacromolecules. 2014 May 12;15(5):1687-95. doi: 10.1021/bm500101w. Epub 2014 Apr 15.
We introduce a novel class of membrane active peptidomimetics, the amphiphilic cationic β(3R3)-peptides, and evaluate their potential as antimicrobial agents. The design criteria, the building block and oligomer synthesis as well as a detailed structure-activity relationship (SAR) study are reported. Specifically, infrared reflection absorption spectroscopy (IRRAS) was employed to investigate structural features of amphiphilic cationic β(3R3)-peptide sequences at the hydrophobic/hydrophilic air/liquid interface. Furthermore, Langmuir monolayers of anionic and zwitterionic phospholipids have been used to model the interactions of amphiphilic cationic β(3R3)-peptides with prokaryotic and eukaryotic cellular membranes in order to predict their membrane selectivity and elucidate their mechanism of action. Lastly, antimicrobial activity was tested against Gram-positive M. luteus and S. aureus as well as against Gram-negative E. coli and P. aeruginosa bacteria along with testing hemolytic activity and cytotoxicity. We found that amphiphilic cationic β(3R3)-peptide sequences combine high and selective antimicrobial activity with exceptionally low cytotoxicity in comparison to values reported in the literature. Overall, this study provides further insights into the SAR of antimicrobial peptides and peptidomimetics and indicates that amphiphilic cationic β(3R3)-peptides are strong candidates for further development as antimicrobial agents with high therapeutic index.
我们介绍了一类新型的膜活性拟肽，即两亲性阳离子β(3R3)-肽，并评估了它们作为抗菌剂的潜力。报告了设计标准、构建块和低聚物合成以及详细的结构-活性关系 (SAR) 研究。具体来说，使用红外反射吸收光谱 (IRRAS) 研究了两亲性阳离子β(3R3)-肽序列在疏水/亲水空气/液体界面处的结构特征。此外，还使用阴离子和两性离子磷脂的 Langmuir 单层来模拟两亲性阳离子β(3R3)-肽与原核和真核细胞膜的相互作用，以预测它们的膜选择性并阐明其作用机制。最后，测试了针对革兰氏阳性菌 M. luteus 和 S. aureus 以及革兰氏阴性菌 E. coli 和 P. aeruginosa 的抗菌活性，同时还测试了溶血活性和细胞毒性。我们发现，与文献报道的值相比，两亲性阳离子β(3R3)-肽序列具有高选择性抗菌活性和极低的细胞毒性。总体而言，这项研究进一步深入了解了抗菌肽和拟肽的 SAR，并表明两亲性阳离子β(3R3)-肽是作为具有高治疗指数的抗菌剂进一步开发的有力候选物。
