Antimicrobial activity of small beta-peptidomimetics based on the pharmacophore model of short cationic antimicrobial peptides.
We have synthesized a series of small beta-peptidomimetics (M(w) <650) that were based on the minimal pharmacophore model for anti-Staphylococcal activity of short cationic antimicrobial peptides. All beta-peptidomimetics had a net charge of +2 and formed an amphipathic scaffold consisting of an achiral lipophilic beta(2,2)-amino acid coupled to a C-terminal l-arginine amide residue. By varying the lipophilic side-chains of the beta(2,2)-amino acids, we obtained a series of highly potent beta-peptidomimetics with high enzymatic stability against alpha-chymotrypsin and a general low toxicity against human erythrocytes. The most potent beta-peptidomimetics displayed minimal inhibitory concentrations of 2.1-7.2 muM against Staphylococcus aureus, methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant Staphylococcus epidermidis (MRSE), and Escherichia coli. Small amphipathic beta-peptidomimetics may be a promising class of antimicrobial agents by means of having a similar range of potency and selectivity as larger cationic antimicrobial peptides in addition to improved enzymatic stability and lower costs of production.
Hansen
Terkel
T
Department of Pharmacy, Faculty of Health Sciences, University of Tromsø, N-9037 Tromsø, Norway.
Alst
Tore
T
Havelkova
Martina
M
Strøm
Morten B
MB
D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry; D002918:Chymotrypsin / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004912:Erythrocytes / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects
D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D009842:Oligopeptides; D002918:Chymotrypsin; C117608:alpha-chymotrypsin