Structure-activity relationships of antibacterial acyl-lysine oligomers.
We describe structure-activity relationships that emerged from biophysical data obtained with a library of antimicrobial peptide mimetics composed of 103 oligoacyllysines (OAKs) designed to pin down the importance of hydrophobicity (H) and charge (Q). Based on results obtained with OAKs displaying minimal inhibitory concentration < or = 3 microM, the data indicate that potent inhibitory activity of the gram-negative Escherichia coli and the gram-positive Staphylococcus aureus required a relatively narrow yet distinct window of HQ values where the acyl length played multiple and critical roles, both in molecular organization and in selective activity. Thus, incorporation of long-but not short-acyl chains within a peptide backbone is shown to lead to rigid supramolecular organization responsible for poor antibacterial activity and enhanced hemolytic activity. However, sequence manipulations, including introduction of a tandem lysine motif into the oligomer backbone, enabled disassembly of aggregated OAKs and subsequently revealed tiny, nonhemolytic, yet potent antibacterial derivatives.
Radzishevsky
Inna S
IS
Department of Biotechnology & Food Engineering, Technion-Israel Institute of Technology, Haifa 32000, Israel.
Kovachi
Tchelet
T
Porat
Yaara
Y
Ziserman
Lior
L
Zaknoon
Fadia
F
Danino
Dganit
D
Mor
Amram
A
D000215:Acylation; D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D006461:Hemolysis / Q000187:drug effects; D057927:Hydrophobic and Hydrophilic Interactions; D008826:Microbial Sensitivity Tests; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D000900:Anti-Bacterial Agents; D009842:Oligopeptides