Antibacterial isoamphipathic oligomers highlight the importance of multimeric lipid aggregation for antibacterial potency
Antibacterial isoamphipathic oligomers highlight the importance of multimeric lipid aggregation for antibacterial potency
复制标题
DOI：
10.1038/s42003-018-0230-4
复制
发表时间：
2018-01-01
影响因子：
5.9
通讯作者：
Alabi, Christopher A.
中科院分区：
文献类型：
--
作者：
Brown, Joseph S.;Mohamed, Zeinab J.;Alabi, Christopher A.
阳离子电荷和疏水性长期以来被理解为驱动抗微生物肽（AMP）的效力和选择性。然而，这些特性本身难以指导体内的广泛成功，其中AMP必须区分细菌和哺乳动物细胞，同时避免复杂的屏障。描述膜破裂的生物物理过程的新参数可以为抗菌剂优化提供新的机会。在这项工作中，我们利用低聚硫醚酰胺（oligoTEAs），以探索膜靶向机制的低聚物，具有相同的阳离子电荷和疏水性，但显示出独特的类似10倍的抗菌效力的差异。溶液相表征揭示了结构和动力学的差异不大。然而，寡聚体处理的金黄色葡萄球菌模拟膜的荧光显微镜显示与生物活性相关的多聚体脂质聚集，并有助于建立动力学作用机制的框架。表面等离子体共振支持动力学框架，并支持脂质聚集作为抗微生物功能的驱动器。
Cationic charge and hydrophobicity have long been understood to drive the potency and selectivity of antimicrobial peptides (AMPs). However, these properties alone struggle to guide broad success in vivo, where AMPs must differentiate bacterial and mammalian cells, while avoiding complex barriers. New parameters describing the biophysical processes of membrane disruption could provide new opportunities for antimicrobial optimization. In this work, we utilize oligothioetheramides (oligoTEAs) to explore the membrane-targeting mechanism of oligomers, which have the same cationic charge and hydrophobicity, yet show a unique similar to 10-fold difference in antibacterial potency. Solution-phase characterization reveals little difference in structure and dynamics. However, fluorescence microscopy of oligomer-treated Staphylococcus aureus mimetic membranes shows multimeric lipid aggregation that correlates with biological activity and helps establish a framework for the kinetic mechanism of action. Surface plasmon resonance supports the kinetic framework and supports lipid aggregation as a driver of antimicrobial function.