Medical University of Gdańsk, Faculty of Pharmacy, Department of Physical Chemistry, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland.
Medical University of Gdańsk, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland.
Biochim Biophys Acta Biomembr. 2019 Jan;1861(1):93-99. doi: 10.1016/j.bbamem.2018.08.013. Epub 2018 Aug 25.
Short cationic lipopeptides are amphiphilic molecules that exhibit antimicrobial activity mainly against Gram-positives. These compounds bind to bacterial membranes and disrupt their integrity. Here we examine the structure-activity relation (SAR) of lysine-based lipopeptides, with a prospect to rationally design more active compounds. The presented study aims to explain how antimicrobial activity of lipopeptides is affected by the charge of lipopeptide headgroup and the length of lipopeptide acyl chain. The obtained SAR models suggest that the lipophilicity of short synthetic cationic lipopeptides is the major factor that determines their antimicrobial activities. In order to link the differences in antimicrobial activity to the mechanism of action of lipopeptides containing one and two hydrophobic chains, we additionally performed molecular dynamic (MD) simulations. By using combined coarse-grained and all-atom simulations we also show that these compounds neither affect the organization of the membrane lipids nor aggregate to form separate phases. These results, along with the onset of antimicrobial activity of lipopeptides well below the critical micelle concentration (CMC), indicate that lipopeptides do not act in a simple detergent-like manner.
短链阳离子脂肽是两亲性分子，主要对革兰氏阳性菌表现出抗菌活性。这些化合物与细菌膜结合并破坏其完整性。在这里，我们研究了赖氨酸脂肽的结构-活性关系（SAR），以期合理设计更具活性的化合物。本研究旨在解释脂肽头部基团的电荷和脂肽酰链长度如何影响脂肽的抗菌活性。所得到的 SAR 模型表明，短合成阳离子脂肽的亲脂性是决定其抗菌活性的主要因素。为了将抗菌活性的差异与含有一个和两个疏水链的脂肽的作用机制联系起来，我们还进行了分子动力学（MD）模拟。通过使用组合的粗粒度和全原子模拟，我们还表明这些化合物既不影响膜脂质的组织，也不会聚集形成单独的相。这些结果，以及脂肽的抗菌活性远低于临界胶束浓度（CMC），表明脂肽的作用方式并非简单的去污剂。
