Development of New Antimicrobial Peptides by Integrating Structural Motifs from Microbial-Derived Cyclic Lipopeptides

Microbial-derived cyclic-lipid antimicrobial peptides (CLAMPs) exhibit significant toxicity, which hinders their wide application in clinical practice. However, such AMPs generally possess high antimicrobial activity and high metabolic stability. The superiority of their molecular structures merits summarization and can be utilized in the design of novel AMPs. Therefore, a heptameric CLAMP template was designed from scratch in this study, with the general formula: R-Dab-(x)-DTyr-cyclo[Lys-y-y-Trp-z-z-Glu]. Through modifying the N-terminal acyl group and amino acids at key positions inside and outside the ring, new CLAMPs with high antimicrobial activity, low toxicity, and high stability were screened out. Among these, the newly optimized CLAMPs, CyLip-10 and CyLip-20, stand out for their broad-spectrum antimicrobial efficacy, low hemolytic activity, and excellent stability. Additionally, they have good safety and antimicrobial activity in vivo. In summary, designing novel CLAMPs based on those derived from microorganisms is feasible and effective.