Abstract：
The increasingly severe bacterial resistance worldwide pushes people to discover and design potential antibacterial drugs unavoidably. In this work, a series of short, mirror-symmetric peptides were designed and successfully synthesized, centered on \"RRR\" and labeled with hydrophobic amino acids at both ends. Based on the structure-activity relationship analysis, LWWR (LWWRRRWWL-NH2) was screened as a desirable mirror-symmetric peptide for further study. As expected, LWWR displayed broad-spectrum antibacterial activity against the standard bacteria and antibiotic-resistant strains. Undoubtedly, the high stability of LWWR in a complex physiological environment was an essential guarantee to maximizing its antibacterial activity. Indeed, LWWR also exhibited a rapid bactericidal speed and a low tendency to develop bacterial resistance, based on the multiple actions of non-receptor-mediated membrane actions and intra-cellular mechanisms. Surprisingly, although LWWR showed similar in vivo antibacterial activity compared with Polymyxin B and Melittin, the in vivo safety of LWWR was far higher than that of them, so LWWR had better therapeutic potential. In summary, the desirable mirror-symmetric peptide LWWR was promised as a potential antibacterial agent to confront the antibiotics resistance crisis. STATEMENT OF SIGNIFICANCE: Witnessing the growing problem of antibiotic resistance, a series of short, mirror-symmetric peptides based on the symmetric center \"RRR\" and hydrophobic terminals were designed and synthesized in this study. Among, LWWR (LWWRRRWWL-NH2) presented broad-spectrum antibacterial activity both in vitro and in vivo due to its multiple mechanisms and good stability. Meanwhile, the low drug resistance and toxicity of LWWR also suggested its potential for clinical application. The findings of this study will provide some inspiration for the design and development of potential antibacterial agents, and contribute to the elimination of bacterial infections worldwide as soon as possible.
摘要：
世界范围内日益严重的细菌耐药性促使人们不可避免地发现和设计潜在的抗菌药物。在这项工作中,一系列简短的，设计并成功合成了镜像对称肽，以“RRR”为中心，两端用疏水氨基酸标记。基于结构-活动关系分析,筛选LWWR(LWWRRWWL-NH2)作为理想的镜像对称肽用于进一步研究。不出所料,LWWR对标准细菌和抗生素抗性菌株显示出广谱抗菌活性。毫无疑问,LWWR在复杂的生理环境中的高稳定性是其抗菌活性最大化的重要保证。的确,LWWR还表现出快速的杀菌速度和低的细菌耐药性倾向，基于非受体介导的膜作用和细胞内机制的多重作用。令人惊讶的是,尽管与多粘菌素B和蜂毒素相比，LWWR显示出相似的体内抗菌活性，LWWR的体内安全性远高于它们，所以LWWR有更好的治疗潜力。总之,理想的镜像对称肽LWWR有望作为一种潜在的抗菌药物来应对抗生素耐药危机.重要性声明：见证抗生素耐药性日益严重的问题，一系列简短的，本研究设计并合成了基于对称中心“RRR”和疏水末端的镜像对称肽。其中,LWWR（LWWRRWWL-NH2）由于其多种机制和良好的稳定性，在体外和体内均具有广谱抗菌活性。同时,LWWR的低耐药性和毒性也表明了其临床应用的潜力。这项研究的结果将为潜在的抗菌剂的设计和开发提供一些启示，并有助于在全球范围内尽快消除细菌感染。
