title: Cell selectivity and mechanism of action of short antimicrobial peptides designed from the cell-penetrating peptide Pep-1.
abstract: Pep-1-K (PK) is a good cell-selective antimicrobial peptide designed from cell-penetrating peptide Pep-1. To develop novel short antimicrobial peptides with higher cell selectivity and shorter length compared with PK, several PK analogs were designed by the deletion, addition and/or substitution of amino acids. Among these analogs, PK-12-KKP (KKPWWKPWWPKWKK) showing the sequence and structure homology with a Trp/Pro-rich natural antimicrobial peptide, indolicidin (IN), displayed a 20-fold higher cell selectivity as compared to IN. Circular dichroism analysis revealed that PK-12-KKP adopts a folded structure combined with some portions of unordered structure. PK-12-KKP selectively binds to negatively charged bacterial membrane-mimetic vesicles, and its high phospholipid selectivity corresponds well with its high cell selectivity. Moreover, it showed very weak potential in depolarization of the cytoplasmic membrane of Staphylococcus aureus at 8 microM (4x minimal inhibitory concentration) and dye leakage from negatively charged liposomes. These results suggest that the ultimate target of our designed PK-12-KKP maybe the intracellular components (e.g. protein, DNA or RNA) rather than the cytoplasmic membranes. Collectively, our designed short Trp/Pro-rich peptide, PK-12-KKP, appears to be an excellent candidate for future development as a novel antimicrobial agent.
authors.affiliation: Department of Bio-Materials, Graduate School and Research Center for Proteineous Materials, Chosun University, Gwangju 501-759, Korea.
authors.forename: Wan Long
authors.initials: WL
authors.lastname: Zhu
authors.forename: Kyung-Soo
authors.initials: KS
authors.lastname: Hahm
authors.forename: Song Yub
authors.initials: SY
authors.lastname: Shin
mesh_terms: D000595:Amino Acid Sequence; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D002462:Cell Membrane / Q000187:drug effects; D002478:Cells, Cultured; D002942:Circular Dichroism; D003543:Cysteamine / Q000031:analogs & derivatives* / Q000737:chemistry; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D013211:Staphylococcus aureus / Q000187:drug effects
chemical_list: D023181:Antimicrobial Cationic Peptides; C503924:Pep-1 peptide; D010455:Peptides; D003543:Cysteamine