Molecular Biophysics, Zernike Institute for Advanced Materials, Rijksuniversiteit Groningen, Groningen, the Netherlands.
Molecular Dynamics, Groningen Biomolecular Sciences & Biotechnology Institute, Rijksuniversiteit Groningen, Groningen, the Netherlands.
Nat Commun. 2023 Jul 7;14(1):4038. doi: 10.1038/s41467-023-39726-5.
Antimicrobial resistance is one of the leading concerns in medical care. Here we study the mechanism of action of an antimicrobial cationic tripeptide, AMC-109, by combining high speed-atomic force microscopy, molecular dynamics, fluorescence assays, and lipidomic analysis. We show that AMC-109 activity on negatively charged membranes derived from Staphylococcus aureus consists of two crucial steps. First, AMC-109 self-assembles into stable aggregates consisting of a hydrophobic core and a cationic surface, with specificity for negatively charged membranes. Second, upon incorporation into the membrane, individual peptides insert into the outer monolayer, affecting lateral membrane organization and dissolving membrane nanodomains, without forming pores. We propose that membrane domain dissolution triggered by AMC-109 may affect crucial functions such as protein sorting and cell wall synthesis. Our results indicate that the AMC-109 mode of action resembles that of the disinfectant benzalkonium chloride (BAK), but with enhanced selectivity for bacterial membranes.
抗菌药物耐药性是医疗保健领域的主要关注点之一。在这里，我们通过结合高速原子力显微镜、分子动力学、荧光分析和脂质组学分析，研究了一种抗菌阳离子三肽 AMC-109 的作用机制。我们表明，AMC-109 对金黄色葡萄球菌衍生的带负电荷的膜的活性由两个关键步骤组成。首先，AMC-109 自组装成由疏水性核心和阳离子表面组成的稳定聚集体，对带负电荷的膜具有特异性。其次，在掺入膜后，单个肽插入到外单层中，影响侧向膜组织并溶解膜纳米区，而不会形成孔。我们提出，AMC-109 引发的膜域溶解可能会影响蛋白质分拣和细胞壁合成等关键功能。我们的结果表明，AMC-109 的作用模式类似于消毒剂苯扎氯铵 (BAK)，但对细菌膜具有更高的选择性。
