Designing peptide amphiphiles as novel antibacterials and antibiotic adjuvants against gram-negative bacteria
Designing peptide amphiphiles as novel antibacterials and antibiotic adjuvants against gram-negative bacteria
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DOI：
10.1016/j.bmc.2023.117481
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发表时间：
2023-09-28
影响因子：
3.5
通讯作者：
de Almeida，Nathalia Rodrigues
中科院分区：
文献类型：
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作者：
Xing，Huihua;Loya-Perez，Vanessa;de Almeida，Nathalia Rodrigues
革兰氏阴性菌株由于其外膜的坚固和不可渗透的特性而对大多数抗生素具有内在抗性。自组装阳离子肽两亲物（PA）具有破坏细菌膜的能力，构成了小分子药物的优良抗菌替代物，其可以单独使用或作为抗生素佐剂来克服细菌耐药性。PA1（C16KHKHK）自组装成胶束，其对所有测试的菌株表现出低的抗菌活性，并且与万古霉素组合显示出强的协同抗菌活性，其对E的部分抑制浓度指数（FICi）为0.15。分子PA2（C16KRKR）和PA3（C16AAAKRKR）也自组装成胶束，对所有测试的菌株显示出广谱抗菌活性，并且在21天内对抗性发展的敏感性较低。最后，PA 1、PA 2和PA 3对哺乳动物细胞表现出较低的细胞毒性，PA 2在使用G的初步体内模型中表现出较强的抗菌活性和较低的毒性。梅隆内拉结果表明，PA是未来开发有效抗生素以减缓抗生素耐药性的一个很好的平台，并且可以作为具有协同作用机制的抗生素佐剂，其可以与现有的常用抗生素一起用于治疗革兰氏阳性菌以治疗革兰氏阴性菌引起的感染。
Gram-negative strains are intrinsically resistant to most antibiotics due to the robust and impermeable characteristic of their outer membrane. Self-assembling cationic peptide amphiphiles (PAs) have the ability to disrupt bacteria membranes, constituting an excellent antibacterial alternative to small molecule drugs that can be used alone or as antibiotic adjuvants to overcome bacteria resistance. PA1 (C16KHKHK), self-assembled into micelles, which exhibited low antibacterial activity against all strains tested, and showed strong synergistic antibacterial activity in combination with Vancomycin with a Fractional Inhibitory Concentration index (FICi) of 0.15 againstE. coli.The molecules, PA2 (C16KRKR) and PA3 (C16AAAKRKR), also self-assembled into micelles, displayed a broad-spectrum antibacterial activity against all strains tested, and low susceptibility to resistance development over 21 days. Finally, PA1, PA 2 and PA3 displayed low cytotoxicity against mammalian cells, and PA2 showed a potent antibacterial activity and low toxicity in preliminaryin vivomodels usingG. mellonella. The results show that PAs are a great platform for the future development of effective antibiotics to slow down the antibiotic resistance and can act as antibiotic adjuvants with synergistic mechanism of action, which can be repurposed for use with existing antibiotics commonly used to treat gram-positive bacteria to treat infections caused by gram-negative bacteria.