Structural Insights Into Papain-Derived Synthetic Antibacterial Peptides for Targeting Klebsiella pneumoniae

Abstract

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.