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.