School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, P. R. China.
National Engineering Research Centre for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou 510006, P. R. China.
Sci Adv. 2024 Aug 30;10(35):eadn9435. doi: 10.1126/sciadv.adn9435.
The fundamental differences in phospholipids between bacterial and mammalian cell membranes present remarkable opportunities for antimicrobial design. However, it is challenging to distinguish bacterial anionic phospholipid phosphatidylglycerol (PG) from mammalian anionic phosphatidylserine (PS) with the same net charge. Here, we report a class of radially amphiphilic α helix antimicrobial peptides (RAPs) that can selectively discriminate PG from PS, relying on the helix structure. The representative RAP, L-MMBen, can direct the rearrangement of PG vesicles into a lamellar structure with its helix axis parallel to the PG membrane surface. The helical structure imparts both the thermodynamic and kinetic advantages of L-MMBen/PG assembly, and the hiding of hydrophobic regions in RAPs is crucial for PG recognition. L-MMBen exhibits high selectivity against bacteria depending on PG recognition, showing low in vivo toxicity and significant treatment efficacy in mice infection models. Our study introduces a helicity-direct bacterial phospholipid recognition paradigm for designing highly selective antimicrobial peptides.
细菌和哺乳动物细胞膜中磷脂的根本差异为抗菌药物设计带来了显著的机遇。然而，具有相同净电荷的细菌阴离子磷脂磷脂酰甘油 (PG) 与哺乳动物阴离子磷脂酰丝氨酸 (PS) 很难区分。在这里，我们报告了一类具有径向两亲性的α螺旋抗菌肽（RAPs），它们可以依靠螺旋结构选择性地区分 PG 与 PS。代表性的 RAP，L-MMBen，可以指导 PG 囊泡重排为层状结构，其螺旋轴与 PG 膜表面平行。螺旋结构赋予了 L-MMBen/PG 组装的热力学和动力学优势，并且 RAPs 中疏水区的隐藏对于 PG 的识别至关重要。L-MMBen 对细菌具有高选择性，这取决于对 PG 的识别，其在体内的毒性低，在小鼠感染模型中具有显著的治疗效果。我们的研究为设计高选择性抗菌肽引入了一种螺旋定向细菌磷脂识别范例。
