The emergence of bacterial multidrug resistance and the lack of new antimicrobial agents urgently demand the discovery and development of novel antibacterials that avoid bacterial resistance. Antimicrobial peptidomimetics represent a promising approach for overcoming antibiotic resistance. Herein we report the synthesis and evaluation of indole-based amphiphilic antimicrobial peptidomimetics, bearing hydrophobic side chains and hydrophilic cationic moieties. Among these derivatives, compound 28 demonstrated potent antimicrobial activity against Gram-positive bacteria, low hemolytic activity and low toxicity towards mammalian cells, as well as good stability in salt conditions. Moreover, compound 28 showed the rapid killing of bacteria via membrane-targeting action without developing bacterial resistance. More importantly, compound 28 displayed high antimicrobial potency against Gram-positive bacteria in a murine model of bacterial keratitis, and was found to be more efficient than vancomycin. Thus, compound 28 had great potential as a promising lead compound for the treatment of Gram-positive bacterial infection.

细菌多药耐药性的出现和新型抗菌药物的缺乏迫切需要发现和开发能够避免细菌耐药性的新型抗菌药物。抗菌肽模拟物代表了一种有前景的克服抗生素耐药性的方法。在此，我们报告了基于吲哚的两亲抗菌肽模拟物的合成和评估，该肽模拟物具有疏水侧链和亲水阳离子部分。在这些衍生物中，化合物28表现出对革兰氏阳性菌的有效抗菌活性、对哺乳动物细胞的低溶血活性和低毒性，以及在盐条件下的良好稳定性。此外，化合物28显示通过膜靶向作用快速杀死细菌而不会产生细菌耐药性。更重要的是，化合物28在细菌性角膜炎小鼠模型中显示出对革兰氏阳性细菌的高抗菌效力，并且被发现比万古霉素更有效。因此，化合物28作为治疗革兰氏阳性细菌感染的有前途的先导化合物具有巨大的潜力。