Background: In the last years, Antimicrobial Peptides (AMPs) and lipopeptides have
received attention as promising candidates to treat infections caused by resistant microorganisms.
Objective: The main objective of this study was to investigate the effect of repetitive KLFK motifs
and the attachment of aliphatic acids to the N-terminus of (KLFK)n peptides on therapeutic properties.
Methods: Minimal inhibitory concentration against Gram (+) and (-) bacteria and yeast of synthetic
compounds were determined by broth microtiter dilution method, and the toxicity was evaluated by
hemolysis assay. Membrane-peptide interaction studies were performed with model phospholipid
membranes mimicking those of bacterial and mammalian cells by Fluorescence Spectroscopy. The
secondary structure in solution and membranes was determined by Circular Dichroism.
Results: Our results showed that the resulting compounds have inhibitory activity against bacteria
and fungi. The (KLFK)3 peptide showed the highest therapeutic index against bacterial and yeast
strains, and the (KLFK)2 peptide conjugated with octanoic acid was the most active against yeasts.
All the lipopeptides containing long-chain fatty acids (C14 or longer) were highly hemolytic at low
concentrations. The antimicrobial activity of (KLFK)2 and (KLFK)3 lipopeptides was mainly
associated with improved stability of the amphipathic secondary structure, which showed high contributions
of α-helix in dipalmitoylphosphatidylglycerol (DPPG) vesicles.
Conclusion: The repetition of the KLFK sequence and the conjugation with lipid tails allowed obtained
compounds with high antimicrobial activity and low toxicity, becoming good candidates for
treating infectious diseases.