Tuning the antimicrobial pharmacophore to enable discovery of short lipopeptides with multiple modes of action

• A series of short arginine, lysine and tryptophan containing lipopeptides have been designed and synthesized.
• Their antimicrobial activities were evaluated against Staphylococcus aureus, Escherichia coli, and Candida albicans.
• The hemolytic effects of these peptides were tested.
• The structure and activity relationships of these peptides were discussed.
• Peptides C10-RKWWK showed a good antimicrobial activity, moderate cytotoxicity and multiple modes of action.

Tryptophan and arginine rich antimicrobial peptides (AMPs) possess high potencies against both gram positive and gram negative bacteria, while lipopeptides represent another family of promising antimicrobial agents to combat invading pathogens. In the present study, we have synthesized a series of very short arginine, lysine and tryptophan containing lipopeptides and evaluated their antimicrobial activities against a panel of pathogenic microorganisms including Staphylococcus aureus, Escherichia coli, and Candida albicans. The results showed that most of these peptides were effective against tested strains with MIC values ranging from 3.9 to 62.5 μg/mL. In addition to the small size, potent bactericidal activity, low to moderate hemolytic toxicity and membrane disruption ability, several peptides such as C10-RIKWWK and C10-RKWWK apparently retarded the migration of DNA on agarose gel in the DNA-binding assay, which implied the multiple modes of action in their bacteria-killing mechanism. These peptides revealed a promising therapeutic potential to develop as new antimicrobial agents.

A series of short lipopeptides have been synthesized and evaluated for their antimicrobial activity. C10-RKWWK and C10-RIKWWK showed the DNA-binding potential and membrane disruption ability in addition to the potent antimicrobial activities.Figure optionsDownload as PowerPoint slide