An antimicrobial peptide as a potential therapy for bacterial pneumonia that alleviates antimicrobial resistance.

Bacterial pneumonia remains a global health threat that is worsened by drug-resistant bacteria, underscoring the need for the development of new antimicrobial agents. Antimicrobial peptides are promising new candidates with broad-spectrum activity and low potential for resistance development. Here, we report a linear antimicrobial peptide (AMP) that consists of four repeating units of (D-tryptophan)-(D-arginine)-(D-lysine). This peptide exhibits high stability and robust antimicrobial activity against multidrug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus and Klebsiella pneumoniae, and improved biocompatibility. Furthermore, the AMP shows low potential for resistance development and the ability to alleviate resistance and restore antibiotic sensitivity due to multiple mechanisms, including membrane targeting and non-membrane lysis (DNA binding, reactive oxygen species accumulation, ATP depletion, metabolic interference). In vivo, the peptide showed promising therapeutic efficacy in a model of methicillin-resistant Staphylococcus aureus and K. pneumoniae pneumonia, as well as in a lipopolysaccharide-induced lung injury model.