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In order to investigate the effects of the double replacement of L-Pro, D-Pro, D-Leu or Nleu (the peptoid residue for Leu) in the hydrophobic face (positions 9 and 13) of amphipathic α-helical non-cell-selective antimicrobial peptide L8K9W1 on the structure, cell selectivity and mechanism of action, we synthesized a series of L8K9W1 analogs with double replacement of L-Pro, D-Pro, D-Leu or Nleu in the hydrophobic face of L8K9W1. In this study, we have confirmed that the double replacement of L-Pro, D-Pro, or Nleu in the hydrophobic face of L8K9W1 let to a great increase in the selectivity toward bacterial cells and a complete destruction of α-helical structure. Interestingly, L8K9W1-L-Pro, L8K9W1-D-Pro and L8K9W1-Nleu preferentially interacted with negatively charged phospholipids, but unlike L8K9W1 and L8K9W1-D-Leu, they did not disrupt the integrity of lipid bilayers and depolarize the bacterial cytoplasmic membrane. These results suggested that the mode of action of L8K9W1-L-Pro, L8K9W1-D-Pro and L8K9W1-Nleu involves the intracellular target other than the bacterial membrane. In particular, L8K9W1-L-Pro, L8K9W1-D-Pro and L8K9W1-Nleu had powerful antimicrobial activity (MIC range, 1 to 4 μM) against methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Pseudomonas aeruginosa (MDRPA). Taken together, our results suggested that L8K9W1L-Pro, L8K9W1-D-Pro and L8K9W1-Nleu with great cell selectivity may be promising candidates for novel therapeutic agents, complementing conventional antibiotic therapies to combat pathogenic microorganisms.

bulletin of the korean chemical society

Effect of Double Replacement of L-Pro, D-Pro, D-Leu or Nleu in Hydrophobic Face of Amphipathic α-Helical Model Antimicrobial Peptide on Structure, Cell Selectivity and Mechanism of Action