Antibacterial peptidomimetics via fragment display on small-molecule scaffolds

Abstract

In response to the growing threat of antimicrobial resistance, scaffold-based peptidomimetics were explored as potential antibacterial agents. This innovative design approach involved fragment display on small-molecule scaffolds of ultrashort peptides and peptidomimetics with alternating cationic/hydrophobic motifs. Compounds, based on ultrashort peptides or peptide/β-peptoid hybrids attached to small-molecule scaffolds comprising bis-, tris-, and tetrakis(bromomethyl)benzene derivatives as well as triamines, were tested for antibacterial activity against a panel of Gram-negative and Gram-positive pathogenic bacteria. Several compounds demonstrated minimal inhibitory concentrations (MICs) of ≤8 μg/mL (~ below 3 μM) against at least one of the tested species. Almost full activity was retained against drug-resistant E. coli, and at 2 × MIC a bactericidal mechanism was found in E. coli. Haemolysis and cell viability assays (at 400 μg/mL) revealed that several compounds possessed an acceptable safety window. These findings highlight the promise of scaffold-based peptidomimetics as novel antibacterial agents and that further studies are warranted.