Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
School of Biomedical Sciences, Queensland University of Technology, Translational Research Institute, ARC Centre of Excellence for Peptides & Protein Science, Brisbane, Queensland 4102, Australia.
Biochim Biophys Acta Gen Subj. 2022 Aug;1866(8):130156. doi: 10.1016/j.bbagen.2022.130156. Epub 2022 May 10.
Arenicin-3 is an amphipathic β-hairpin antimicrobial peptide that is produced by the lugworm Arenicola marina. In this study, we have investigated the mechanism of action of arenicin-3 and an optimized synthetic analogue, AA139, by studying their effects on lipid bilayer model membranes and Escherichia coli bacterial cells. The results show that simple amino acid changes can lead to subtle variations in their interaction with membranes and therefore alter their pre-clinical potency, selectivity and toxicity. While the mechanism of action of arenicin-3 is primarily dependent on universal membrane permeabilization, our data suggest that the analogue AA139 relies on more specific binding and insertion properties to elicit its improved antibacterial activity and lower toxicity, as exemplified by greater selectivity between lipid composition when inserting into model membranes i.e. the N-terminus of AA139 seems to insert deeper into lipid bilayers than arenicin-3 does, with a clear distinction between zwitterionic and negatively charged lipid bilayer vesicles, and AA139 demonstrates a cytoplasmic permeabilization dose response profile that is consistent with its greater antibacterial potency against E. coli cells compared to arenicin-3.
阿雷西丁-3 是一种两亲性 β-发夹抗菌肽，由沙蚕 Arenicola marina 产生。在这项研究中，我们通过研究它们对脂质双层模型膜和大肠杆菌细胞的影响，研究了阿雷西丁-3 和优化的合成类似物 AA139 的作用机制。结果表明，简单的氨基酸变化可能导致它们与膜的相互作用发生微妙变化，从而改变其临床前效力、选择性和毒性。虽然阿雷西丁-3 的作用机制主要依赖于普遍的膜通透性，但我们的数据表明，类似物 AA139 依赖于更特定的结合和插入特性来发挥其增强的抗菌活性和更低的毒性，例如在插入模型膜时，脂质组成之间的选择性更大，即 AA139 的 N 端似乎比阿雷西丁-3 插入脂质双层更深，带电荷和负电荷脂质双层囊泡之间有明显区别，AA139 表现出细胞质通透性剂量反应曲线，这与其对大肠杆菌细胞的更强抗菌效力一致，与阿雷西丁-3 相比。
