Structural Insights Into Papain‐Derived Synthetic Antibacterial Peptides for Targeting <scp><i>Klebsiella pneumoniae</i></scp>

Bacterial resistance represents one of the greatest challenges in modern medicine, requiring innovative strategies. This study presents the rational design of two synthetic analogue peptides, WK-MAP1, and WG-MAP2, inspired by the structure of the enzyme papain (PDB 9PAP), emphasizing the novelty of using an enzyme as a model for developing new antimicrobials. Initially, in silico studies, including molecular modeling and docking experiments, revealed a high affinity of the peptides for mimetic bacterial membranes. Subsequently, in vitro assays confirmed their antimicrobial efficacy. WK-MAP1 demonstrated superior activity against carbapenem-resistant Klebsiella pneumoniae (KPC+), with a minimum inhibitory concentration (MIC) of 25 μM, whereas WG-MAP2 exhibited activity against both tested strains (KPC+ and ATCC), with MICs of 50 and 100 μM, respectively. Both peptides effectively inhibited biofilm formation and exhibited low cytotoxicity in murine cells. This research highlights the potential of WK-MAP1 and WG-MAP2 as promising candidates for novel antimicrobial therapies, offering an innovative approach to overcoming the limitations of conventional antibiotics.