Lauroylated peptide dendrimers with potent and broad-spectrum antimicrobial activity against multidrug-resistant bacteria.

Abstract

Peptide dendrimers, characterized by their branched structure and densely arrayed surface amino acids or peptides, offer enhanced multivalency and unimolecular stability that collectively improve receptor engagement and bioactivity. Despite these advantages, broad application remains limited due to synthetic complexity, high production costs, and increased toxicity associated with larger dendrimer generations. To address these limitations, this study presents a streamlined design for peptide dendrimers featuring one or two branched heptapeptides tethered to a linear nonapeptide scaffold, with lauric acid introduced to the dendrimer core to drive self-assembly and enhance molecular stability. The resulting construct, designated Lau-IL-9-C2, demonstrated potent and broad-spectrum antibacterial activity against multidrug-resistant strains, alongside high biocompatibility in both in vitro and in vivo models. Mechanistic investigations revealed that Lau-IL-9-C2 exerted bactericidal effects through dual modes of action, not only disrupting bacterial membranes by targeting lipoteichoic acid (LTA), lipopolysaccharide (LPS), and phosphatidylglycerol but also inhibiting intracellular biological processes. Lau-IL-9-C2 also eradicated bacterial biofilms and persister cells and exhibited sustained efficacy without resistance development. In a murine wound infection model, Lau-IL-9-C2 achieved significant therapeutic outcomes, effectively clearing bacterial burden and accelerating wound healing. These findings support the rational design of structurally accessible peptide dendrimers as a promising platform for next-generation antimicrobial therapeutics. STATEMENT OF SIGNIFICANCE: Peptide dendrimers with enhanced multivalency and unimolecular stability that collectively improve bioactivity. However, higher dendrimer generations substantially increase synthetic complexity and production costs. To address these limitations, we present a minimal yet functionally robust branching strategy to construct peptide dendrimers featuring with one or two branched heptapeptides tethered to a linear nonapeptide scaffold, with lauric acid introduced to the dendrimer core to drive self-assembly and enhance molecular stability. The lead peptide dendrimer Lau-IL-9-C2 was identified with potent and broad-spectrum antimicrobial activity against multidrug-resistant bacteria and high biocompatibility in both in vitro and in vivo systems. These findings advance understanding of peptide dendrimer structure-activity relationships and support the development of simplified dendrimer-based antibiotics for the treatment of multidrug-resistant bacterial infections.