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

Abstract

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.

Improved anticancer potency by head‐to‐tail cyclization of short cationic anticancer peptides containing a lipophilic β2,2‐amino acid

“…The two Fmoc‐ β 2,2 ‐amino acids 2a and 2b were synthesized as reported earlier except for the initial dialkylation of methyl cyanoacetate (Scheme ) . The dialkylation was previously performed in two steps by using NaOMe as base.…”

“…Synthesis of Fmoc‐ β 2,2 ‐amino acids and linear peptides were performed as reported earlier, except the initial disubstitution of methyl cyanoacetate . All chemicals were purchased from Sigma‐Aldrich and used without further purification.…”

The effect of glycine replacement with flexible ω-amino acids on the antimicrobial and haemolytic activity of an amphipathic cyclic heptapeptide

“…Amphipathicity and total lipophilicity are often presented as the key parameters determining the biological activity of this type of molecules [51]. However, by comparing pairs of closely related peptides such as 10/11, 12/14 and 15/16, it is clear that total lipophilicity cannot satisfactorily explain the observed changes in biological activity.…”

N-terminal aromatic tag induced self assembly of tryptophan–arginine rich ultra short sequences and their potent antibacterial activity

“…Sequence template approach is among of the most successful ways to design ultra short antimicrobial peptidomimetics based on balance between cationic (+2 to +9 charge) and hydrophobic residues (approximately 50%) [35,36]. Trp residues impart hydrophobicity along with a distinct ability to reside at membrane inter-phase improving antibacterial activity [20].…”