Short, mirror-symmetric antimicrobial peptides centered on "RRR" have broad-spectrum antibacterial activity with low drug resistance and toxicity.

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.