A Novel Gelatinase-Responsive Self-Assembled Antimicrobial Peptide for Combating Drug-Resistant Bacterial Infection

The rising threat of multidrug-resistant bacterial infections demands innovative antimicrobial strategies that combine rapid bactericidal action with minimized resistance development. Despite the promising prospects of antimicrobial peptides (AMPs) due to their rapid bactericidal effect and unique membrane disruption mechanism, toxicity and stability issues have hindered their clinical application. Here, we designed a gelatinase-responsive self-assembled AMP (PEG-PR-26) to overcome the limitations of natural AMPs and to combat methicillin-resistant<i>Staphylococcus aureus</i> (MRSA). Upon exposure to gelatinase at infection sites, PEG-PR-26 releases VR-23 nanoparticles, which disrupt bacterial membranes via rapid complete depolarization and content leakage. The PEGylation strategy enhances serum stability (half-life >24 h vs 9 h for FR-13) and biocompatibility (hemolysis rates <5% at 64 μM). <i>In vivo</i> studies showed that PEG-PR-26 had no obvious toxicity and effectively reduced the extent of lung bacterial infection in mice. Notably, PEG-PR-26 synergizes with antibiotics (Min_FICI = 0.18) and exhibits low resistance development after a 15 day exposure. Overall, this research provides a viable antimicrobial alternative to combat bacterial resistant infections by effectively killing drug-resistant bacteria in mice infected with pneumonia.