Antibacterial agents based on the cyclic D,L-α-peptide architecture
Antibacterial agents based on the cyclic D,L-α-peptide architecture
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DOI：
10.1038/35086601
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发表时间：
2001-07-26
期刊：
影响因子：
64.8
通讯作者：
Ghadiri, MR
中科院分区：
文献类型：
--
作者：
Fernandez-Lopez, S;Kim, HS;Ghadiri, MR
对许多药物具有耐药性的细菌感染的迅速出现强调了对新治疗剂的需求（1-3）。在这里，我们报告说，六个和八个残基的环状D，L-α-肽优先作用于革兰氏阳性和/或革兰氏阴性细菌膜相比，哺乳动物细胞，增加膜通透性，跨膜离子电位崩溃，并导致快速细胞死亡。这类材料作为选择性抗菌剂的有效性通过在小鼠中观察到的针对致死性耐甲氧西林金黄色葡萄球菌感染的高功效而突出。环状D，L-α-肽是蛋白水解稳定的，易于合成，并且可以衍生自潜在的巨大的膜活性序列空间。环肽的独特非生物结构和它们的快速杀菌作用也可能有助于限制耐药细菌的暂时获得。低分子量D，L-α-肽为目前天然衍生的抗生素库提供了有吸引力的补充，并在对抗各种现有和新出现的传染病方面具有相当大的潜力。
The rapid emergence of bacterial infections that are resistant to many drugs underscores the need for new therapeutic agents(1-3). Here we report that six- and eight-residue cyclic D,L-alpha -peptides act preferentially on Gram-positive and/or Gram-negative bacterial membranes compared to mammalian cells, increase membrane permeability, collapse transmembrane ion potentials, and cause rapid cell death. The effectiveness of this class of materials as selective antibacterial agents is highlighted by the high efficacy observed against lethal methicillin-resistant Staphylococcus aureus infections in mice. Cyclic D,L-alpha -peptides are proteolytically stable, easy to synthesize, and can be derived from a potentially vast membrane-active sequence space. The unique abiotic structure of the cyclic peptides and their quick bactericidal action may also contribute to limit temporal acquirement of drug resistant bacteria. The low molecular weight D,L-alpha -peptides offer an attractive complement to the current arsenal of naturally derived antibiotics, and hold considerable potential in combating a variety of existing and emerging infectious diseases.