Engineered Peptides Show Promise Against Drug-Resistant Gram-Negative Bacteria

Gram-negative bacterial infections are a growing global health crisis due to increasing antibiotic resistance, leading to limited treatment options and high mortality rates. Traditional antimicrobial peptides (AMPs) offer a potential alternative, but their widespread clinical application is often hindered by poor in vivo stability, susceptibility to enzymatic degradation, and potential toxicity. This study addresses the critical need for novel AMPs with enhanced stability and potent activity against challenging gram-negative pathogens.

The engineered β-AMPs demonstrated significantly enhanced stability and potent antimicrobial activity. Specifically, the lead candidate, β-AMP-X, showed a minimum inhibitory concentration (MIC) as low as 0.5 µg/mL against Pseudomonas aeruginosa and Acinetobacter baumannii, representing a 2-fold to 4-fold improvement compared to conventional α-AMPs. In vitro stability assays revealed that β-AMP-X exhibited >90% resistance to degradation by trypsin and chymotrypsin after 24 hours, whereas a control α-AMP was <10% intact. Furthermore, β-AMP-X displayed low hemolytic activity, with <5% hemolysis at concentrations up to 100 µg/mL. In the murine infection model, treatment with β-AMP-X at 5 mg/kg resulted in a 3.5-log reduction in bacterial load in the spleen and kidneys, leading to a 75% survival rate compared to 20% in the untreated control group (p<0.001).