Burdach Kinga, Tymecka Dagmara, Urban Aneta, Lasek Robert, Bartosik Dariusz, Sek Slawomir
Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, Żwirki i Wigury 101, 02-089 Warsaw, Poland.
Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland.
Membranes (Basel). 2021 Mar 10;11(3):192. doi: 10.3390/membranes11030192.
The increasing resistance of bacteria to available antibiotics has stimulated the search for new antimicrobial compounds with less specific mechanisms of action. These include the ability to disrupt the structure of the cell membrane, which in turn leads to its damage. In this context, amphiphilic lipopeptides belong to the class of the compounds which may fulfill this requirement. In this paper, we describe two linear analogues of battacin with modified acyl chains to tune the balance between the hydrophilic and hydrophobic portion of lipopeptides. We demonstrate that both compounds display antimicrobial activity with the lowest values of minimum inhibitory concentrations found for Gram-positive pathogens. Therefore, their mechanism of action was evaluated on a molecular level using model lipid films mimicking the membrane of Gram-positive bacteria. The surface pressure measurements revealed that both lipopeptides show ability to bind and incorporate into the lipid monolayers, resulting in decreased ordering of lipids and membrane fluidization. Atomic force microscopy (AFM) imaging demonstrated that the exposure of the model bilayers to lipopeptides leads to a transition from the ordered gel phase to disordered liquid crystalline phase. This observation was confirmed by attenuated total reflection Fourier-transform infrared spectroscopy (ATR-FTIR) results, which revealed that lipopeptide action causes a substantial increase in the average tilt angle of lipid acyl chains with respect to the surface normal to compensate for lipopeptide insertion into the membrane. Moreover, the peptide moieties in both molecules do not adopt any well-defined secondary structure upon binding with the lipid membrane. It was also observed that a small difference in the structure of a lipophilic chain, altering the balance between hydrophobic and hydrophilic portion of the molecules, results in different insertion depth of the active compounds.
细菌对现有抗生素的耐药性不断增加，促使人们寻找作用机制不那么特异的新型抗菌化合物。这些机制包括破坏细胞膜结构，进而导致细胞膜受损。在这种情况下，两亲性脂肽属于可能满足这一要求的化合物类别。在本文中，我们描述了两种具有修饰酰基链的线性巴他杀菌素类似物，以调节脂肽亲水和疏水部分之间的平衡。我们证明这两种化合物均具有抗菌活性，对革兰氏阳性病原体的最低抑菌浓度值最低。因此，我们使用模拟革兰氏阳性细菌膜的模型脂质膜在分子水平上评估了它们的作用机制。表面压力测量结果表明，这两种脂肽都具有结合并融入脂质单层的能力，导致脂质有序性降低和膜流动性增加。原子力显微镜（AFM）成像显示，将模型双层膜暴露于脂肽会导致从有序凝胶相转变为无序液晶相。衰减全反射傅里叶变换红外光谱（ATR-FTIR）结果证实了这一观察结果，该结果表明脂肽的作用会导致脂质酰基链相对于表面法线的平均倾斜角大幅增加，以补偿脂肽插入膜中。此外，两个分子中的肽部分在与脂质膜结合时均未采用任何明确的二级结构。还观察到，亲脂性链结构上的微小差异，改变了分子疏水和亲水部分之间的平衡，导致活性化合物的插入深度不同。
