The threat of antibiotic resistance to community healthcare and the global economy has raised extensive concern, and the over-use of antibiotics in animal husbandry plays a significant role in the occurrence and spread of resistance genes. An emerging solution for the above problem is the development of antimicrobial peptides (AMPs) and their mimics as alternative disinfectants in agriculture and aquaculture. These antibacterial agents usually exhibit excellent potency and a low drug resistance generation rate, but are highly cytotoxic to eukaryotes and thus post safety concerns. Here, we report our solution to this problem by introducing degradable linkers in oligoguanidine-based antimicrobial peptidomimetics with a dual-selective mechanism of action. With both bacterial membrane and DNA targeting capability, the hit peptidomimetic exhibited higher therapeutic indices and synergistic effects with other antibiotics, while its fast antimicrobial kinetics and low resistance rate were maintained. In addition, the added degradable feature improved the biocompatibility and environmental sustainability of this material. The oligoguanidine-based hit peptidomimetic also showed good activity in vivo, as it did not cause observable toxicity in zebrafish, and it could significantly improve the survival rate of zebrafish in a scratch wound infection model.

中文翻译：

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一种可降解、广谱和抗耐药性的抗菌寡胍，作为水产养殖中的消毒和治疗剂

抗生素耐药性对社区医疗保健和全球经济的威胁已引起广泛关注，畜牧业抗生素的过度使用对耐药基因的发生和传播起着重要作用。针对上述问题的一个新兴解决方案是开发抗菌肽 (AMP) 及其模拟物，作为农业和水产养殖中的替代消毒剂。这些抗菌剂通常表现出极好的效力和较低的耐药性产生率，但对真核生物具有高度的细胞毒性，因此存在安全问题。在这里，我们通过在具有双重选择性作用机制的基于寡胍的抗菌肽模拟物中引入可降解接头来报告我们对该问题的解决方案。同时具有细菌膜和 DNA 靶向能力，hit peptidomimetic 表现出更高的治疗指数和与其他抗生素的协同作用，同时保持其快速的抗菌动力学和低耐药率。此外，添加的可降解特性提高了这种材料的生物相容性和环境可持续性。基于寡胍的打击肽模拟物也显示出良好的活性在体内，因为它不会对斑马鱼造成可观察到的毒性，并且可以显着提高斑马鱼在划伤感染模型中的存活率。