title: Design of potent, non-toxic antimicrobial agents based upon the structure of the frog skin peptide, temporin-1CEb from Chinese brown frog, Rana chensinensis.
abstract: Temporin-1CEb shows antimicrobial activity against Gram-positive bacteria, but its therapeutic potential is limited by its haemolysis. In this study, eight temporin-1CEb analogues with altered cationicities and hydrophobicities were synthesized. Increasing cationicity and amphipathicity by substituting neutral and non-polar amino acid residues on the hydrophilic face of the α-helix by five or six lysines increased antimicrobial potency approximately 10-fold to 40-fold, although when the number of positive charges was increased from +6 to +7, the antimicrobial potency was not additionally enhanced. The substitution of an l-lysine with a d-lysine, meanwhile maintaining the net charge and the mean hydrophobicity values, had only a minor effect on its antimicrobial activity, whereas significantly led a decrease in its haemolytic activity. Of all the peptides, l-K6 has the best potential as an antimicrobial agent because its antimicrobial activity against both Gram-positive and Gram-negative bacteria is substantial, and its haemolytic activity is negligible. l-K6 adopts an α-helix in 50% trifluoroethanol/water and 30 mm SDS solutions. l-K6 killed 99.9% of E. coli and S. aureus at 4× MIC in 60 min, and its postantibiotic effect was >5 h. l-K6 affects the integrity of E. coli and S. aureus plasma membranes by rapidly inducing membrane depolarization.
authors.affiliation: Faculty of Life Science, Liaoning Normal University, Dalian, China. djshang@lnnu.edu.cn
authors.forename: Dejing
authors.initials: D
authors.lastname: Shang
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Li
authors.forename: Yue
authors.initials: Y
authors.lastname: Sun
authors.forename: Che
authors.initials: C
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.forename: Shi
authors.initials: S
authors.lastname: Wei
authors.forename: Meng
authors.initials: M
authors.lastname: Gou
mesh_terms: D000595:Amino Acid Sequence; D029845:Amphibian Proteins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D001419:Bacteria / Q000187:drug effects; D001424:Bacterial Infections / Q000188:drug therapy; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D011506:Proteins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D011898:Ranidae / Q000378:metabolism*; D012867:Skin / Q000737:chemistry
chemical_list: D029845:Amphibian Proteins; D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D011506:Proteins; C104501:temporin