Design, synthesis, molecular docking, and antimicrobial evaluation of hybrid peptides incorporating unnatural amino acids with enhanced hydrophobic sidechains

Abstract

The emergence of multidrug-resistant (MDR) pathogens has intensified the need for novel antimicrobial agents. This study focuses on the design, synthesis, and evaluation of hybrid peptides (6a–6e) incorporating unnatural amino acids featuring enhanced hydrophobic side chains. These peptides, particularly 6e, demonstrated potent antimicrobial efficacy. Molecular docking identified the robust binding affinities of peptides 6e and 6b towards the transglycosylase domain of Escherichia coli PBP1b, indicating their potential as enzyme inhibitors. Molecular dynamics (MD) simulations confirmed the stability of peptide-protein complexes over a 100 ns timespan, supporting the structural integrity of peptide 6e. Experimental data further validated computational predictions, with peptide 6e exhibiting minimum inhibitory concentrations (MICs) as low as 2 µg mL⁻¹ against E. coli and 0.2 µg mL⁻¹ against Bacillus subtilis. Additionally, 6e demonstrated broad-spectrum antifungal efficacy, showing competitive activity against Candida albicans and Aspergillus niger. These results establish unnatural amino acid-based peptides as promising candidates in addressing MDR infections, warranting further studies for clinical application.