Journal
CHEMICAL BIOLOGY & DRUG DESIGN
Volume 79, Issue 5, Pages 653-662Publisher
WILEY
DOI: 10.1111/j.1747-0285.2012.01363.x
Keywords
cationicity; depolarization; haemolytic activity; hydrophobicity; membrane integrity
Funding
- National Natural Science Foundation of China [30970352]
- Liaoning Key Laboratory Program [2008S131]
- Liaoning Excellent Talents in University Program [2007R27]
- Dalian Science and Technology Bureau [2011E12SF031]
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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 alpha-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 alpha-helix in 50% trifluoroethanol/water and 30 mm SDS solutions. l-K6 killed 99.9% of E. coli and S. aureus at 4x 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.
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