14-Helical β-Peptides Elicit Toxicity against C. albicans by Forming Pores in the Cell Membrane and Subsequently Disrupting Intracellular Organelles
14-Helical β-Peptides Elicit Toxicity against C. albicans by Forming Pores in the Cell Membrane and Subsequently Disrupting Intracellular Organelles
复制标题
DOI：
10.1016/j.chembiol.2018.11.002
复制
发表时间：
2019-02-21
影响因子：
8.6
通讯作者：
Palecek, Sean P.
中科院分区：
文献类型：
--
作者：
Lee, Myung-Ryul;Raman, Namrata;Palecek, Sean P.
与天然抗菌肽相比，人工合成的抗菌肽具有更强的结构稳定性和蛋白水解性，能促进膜的破坏，是一种很有前途的抗菌药物候选药物。我们先前报道了选择性抗真菌14-螺旋β-肽，但其抗真菌毒性的机制仍不清楚。为了深入了解这一机制，我们研究了抗真菌β-肽与人造膜和白色念珠菌活细胞的结合。我们研究了β-肽与真菌膜的小单层囊泡模型相互作用和渗透的能力。分配系数支持孔中介机制，其特征是存在一个分隔低分配系数和高分配系数区域的临界β-肽浓度。活体细胞内对β-多肽的跟踪表明，β-多肽移位到细胞质中，然后依次破坏细胞核和空泡，导致细胞死亡。这种对抗真菌活性机制的理解将有助于设计和开发模拟多肽的AMP，包括14-螺旋的β-肽，用于抗真菌应用。
Synthetic peptidomimetics of antimicrobial peptides (AMPs) are promising antimicrobial drug candidates because they promote membrane disruption and exhibit greater structural and proteolytic stability than natural AMPs. We previously reported selective antifungal 14-helical beta-peptides, but the mechanism of antifungal toxicity of beta-peptides remains unknown. To provide insight into the mechanism, we studied antifungal beta-peptide binding to artificial membranes and living Candida albicans cells. We investigated the ability of beta-peptides to interact with and permeate small unilamellar vesicle models of fungal membranes. The partition coefficient supported a pore-mediated mechanism characterized by the existence of a critical beta-peptide concentration separating low-and high-partition coefficient regimes. Live cell intracellular tracking of beta-peptides showed that beta-peptides translocated into the cytoplasm, and then disrupted the nucleus and vacuole sequentially, leading to cell death. This understanding of the mechanisms of antifungal activity will facilitate design and development of peptidomimetic AMPs, including 14-helical beta-peptides, for antifungal applications.