| Summary: | DMPC-10A (ALWKKLLKK-Cha-NH<sub>2</sub>) is a 10-mer peptide derivative from the N-terminal domain of Dermaseptin-PC which has shown broad-spectrum antimicrobial activity as well as a considerable hemolytic effect. In order to reduce hemolytic activity and improve stability to endogenous enzymes, a D-amino acid enantiomer (DMPC-10B) was designed by substituting all L-Lys and L-Leu with their respective D-form amino acid residues, while the Ala<sup>1</sup> and Trp<sup>3</sup> remained unchanged. The D-amino acid enantiomer exhibited similar antimicrobial potency to the parent peptide but exerted lower cytotoxicity and hemolytic activity. Meanwhile, DMPC-10B exhibited remarkable resistance to hydrolysis by trypsin and chymotrypsin. In addition to these advantages, DMPC-10B exhibited an outstanding antibacterial effect against Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) and <i>Klebsiella pneumoniae</i> using the <i>Galleria mellonella</i> larva model and displayed synergistic activities with gentamicin against carbapenem-resistant <i>K. pneumoniae</i> strains. This indicates that DMPC-10B would be a promising alternative for treating antibiotic-resistant pathogens.
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