De novo design of short antimicrobial lipopeptides

Abstract

The increase in bacterial resistance to antibiotics available leads to the search for new compounds with antimicrobial potential, such as peptides and lipopeptides. In this work, eight short lipopeptides with the structural pattern Cn-X₁ X₂ X₃-NH₂ were de novo designed, synthesized by Fmoc solid phase and characterized by instrumental techniques. The results of the in vitro tests indicated that two of them, LIP 4 and LIP 12 display antibacterial activity against 4 pathogenic bacteria with minimum inhibitory concentrations (MIC) between 9.50 and 100 μM and between 8.50 and 10.0 μM, respectively; they did not displayed toxicity to human erythrocytes at concentrations between 3.13 and 50.0 μM. The antibacterial mechanism of action observed by scanning electron microscopy indicate that the cell membrane was the target, causing the formation of blisters and vesicles, with size ranging from 100 to 120 nm. The lipopeptide LIP 12, with higher activity, was stable to proteases of human blood serum.

Key words
antimicrobial activity; de novo design; Fmoc synthesis; protease stability; short lipopeptides