Laboratory of Bioelectrochemistry, A.N. Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, 31/4 Leninskiy Prospekt, 119071 Moscow, Russia.
Biomolecules. 2024 Sep 4;14(9):1118. doi: 10.3390/biom14091118.
Antimicrobial peptides (AMPs) are believed to be a prominent alternative to the common antibiotics. However, despite decades of research, there are still no good clinical examples of peptide-based antimicrobial drugs for system application. The main reasons are loss of activity in the human body, cytotoxicity, and low selectivity. To overcome these challenges, a well-established structure-function relationship for AMPs is critical. In the present study, we focused on the well-known examples of melittin and magainin to investigate in detail the initial stages of AMP interaction with lipid membranes at low peptide-to-lipid ratio. By combining the patch-clamp technique with the bioelectrochemical method of intramembrane field compensation, we showed that these peptides interact with the membrane in different ways: melittin inserts deeper into the lipid bilayer than magainin. This difference led to diversity in pore formation. While magainin, after a threshold concentration, formed the well-known toroidal pores, allowing the translocation of the peptide through the membrane, melittin probably induced predominantly pure lipidic pores with a very low rate of peptide translocation. Thus, our results shed light on the early stages of peptide-membrane interactions and suggest new insights into the structure-function relationship of AMPs based on the depth of their membrane insertion.
抗菌肽（AMPs）被认为是抗生素的一种重要替代品。然而，尽管经过了几十年的研究，仍然没有肽类抗菌药物在系统应用方面的良好临床范例。主要原因是在人体中失去活性、细胞毒性和选择性低。为了克服这些挑战，建立 AMP 结构-功能关系至关重要。在本研究中，我们专注于众所周知的蜂毒素和magainin 示例，详细研究了低肽-脂质比下 AMP 与脂质膜相互作用的初始阶段。通过将膜片钳技术与膜内场补偿的生物电化学方法相结合，我们表明这些肽以不同的方式与膜相互作用：蜂毒素比 magainin 更深地插入脂质双层。这种差异导致了孔形成的多样性。虽然 magainin 在达到阈值浓度后形成了众所周知的环形孔，允许肽通过膜转运，但蜂毒素可能主要诱导脂质孔，肽的转运率非常低。因此，我们的结果阐明了肽-膜相互作用的早期阶段，并基于其膜插入的深度，为 AMP 的结构-功能关系提供了新的见解。
