Haloganan: a novel antimicrobial peptide for treatmentof wound infections

HG1 is a Leu-rich antimicrobial peptide (AMP). Previously, the peptide was shown to lose its activity in human serum although it possessed potent and broad spectrum antimicrobial activity against a wide range of pathogenic microbes. In an attempt to design an HG1 isomer that can overcome the problem of HG1, a structure–activity relationship study was conducted by substitution of each of five Leu residues with a Gln residue. Each substitute was tested for its antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA) or Candida strains. In addition, the antimicrobial activity of HG1 isomers was examined in the presence of glycosaminoglycans or lipid components occurring in the extracellular matrix, human serum and wound fluid. As a result, it was determined that the third residue (Leu) in the sequence of HG1 was mainly responsible for abrogation of its antimicrobial activity in human serum or wound fluid. An HG1 isomer (L3Q) with a Gln-3 substitution exhibited a potent antibacterial activity in 50% human serum. While the anti-MRSA activity of L3Q was equivalent to that of HG1, its anti-Candida activity was found to be substantially reduced. In order to improve anti-Candida activity of L3Q, its cationicity was enhanced by replacement of the C-terminal Ala-19 with a Lys residue. Overall, an HG1 isomer with two substitutions of Gln-3 and Lys-19, named haloganan, was verified to have an advantage over HG1 in that it exerted its potent antimicrobial activity under conditions containing human serum and/or wound fluid.