Engineered Protegrin-1 Peptides Overcome Colistin Resistance in Deadly Bacteria

The global rise of antimicrobial resistance (AMR) poses a severe threat to public health, with multidrug-resistant (MDR) bacteria like colistin-resistant Klebsiella pneumoniae (CR-Kp) causing increasingly untreatable infections. Antimicrobial peptides (AMPs), such as protegrin-1, represent a promising class of novel antibiotics, but their full therapeutic potential against highly resistant strains is often limited by structural factors. This study addresses how specific structural modifications to the arginine-rich loop of protegrin-1 can enhance its activity against colistin-resistant pathogens.

The study identified that specific alterations to the charge distribution and local structural constraints within the arginine loop significantly improved protegrin-1's antimicrobial potency. The lead analog, PG-1-ModX, demonstrated an MIC of 0.75 µg/mL against CR-Kp strains, representing a 3.3-fold improvement compared to the native protegrin-1 (MIC 2.5 µg/mL). Furthermore, PG-1-ModX induced 68% greater membrane permeabilization in CR-Kp cells within 60 minutes than the unmodified peptide. In the murine sepsis model, PG-1-ModX treatment led to a remarkable 83% survival rate at 72 hours, significantly higher than the 21% survival observed in the untreated control group (p<0.001). This therapeutic effect was accompanied by a 2.5-log reduction in bacterial load in the spleen and lungs. PG-1-ModX, a structurally optimized protegrin-1 variant, exhibited a 3.3-fold increase in in vitro potency against colistin-resistant Klebsiella pneumoniae and improved survival by 62% in a lethal murine sepsis model.