Antibacterial activity of 15‐residue lactoferricin derivatives

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Abstract
Lactoferricins are a class of antibacterial peptides isolated after gastric‐pepsin digest of the mammalian iron‐chelating‐protein lactoferrin. For investigation of antibacterial activity, we prepared short synthetic derivatives of bovine, human, caprine, murine and porcine lactoferricins with 15‐amino‐acid residues of high sequence homology. The peptides corresponded to amino‐acid residues 17–31 of the mature bovine lactoferrin. Only the bovine and caprine derivatives displayed measurable antibacterial activity, with the bovine one having a minimal inhibitory concentration of 24 µm and being 10 times more active than the caprine one against Escherichia coli. An alanine‐scan of the bovine lactoferricin derivative was performed to identify specific amino acids that were important for the antibacterial activity. We found that neither of the two tryptophan residues (Trp 6 and Trp 8) present in the bovine lactoferricin derivative could be replaced by alanine without a major loss of antibacterial activity. The other lactoferricin derivatives tested contained only one tryptophan residue (Trp 6). Modified human, caprine and porcine lactoferricin derivatives containing two tryptophan residues (Trp 6 and Trp 8) displayed minimal inhibitory concentrations of 74, 174 and 219 µm, respectively, which represented up to a six‐fold increase in antibacterial activity. The alanine‐scan also revealed that the antibacterial activity was increased when acetamidomethyl‐protected cysteine and unprotected glutamine (Cys 3 and Gln 7) were replaced with alanine. Only the bovine lactoferricin derivative and a few of its alanine‐modified derivatives displayed measurable activity against Staphylococcus aureus.