Antimicrobial Activity of Small β-Peptidomimetics Based on the Pharmacophore Model of Short Cationic Antimicrobial Peptides

摘要

We have synthesized a series of small β-peptidomimetics (Mw <650) that were based on the minimal pharmacophore model for anti-Staphylococcal activity of short cation+2 and formed an amphipathic scaffold consisting of an achiral lipophilic β2,2-amino acid coupled to a C-terminal L-arginine amide residue. By varying the lipophilic side-chains of the β2,2-amino acids, we obtained a series of highly potent β-peptidomimetics with high enzymatic stability against R-chymotrypsin and a general low toxicity against human erythrocytes. The most potent β-peptidomimetics displayed minimal inhibitory concentrations of 2.1-7.2 μM against Staphylococcus aureus, methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant Staphylococcus epidermidis (MRSE), and Escherichia coli. Small amphipathic β-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.