Chirality‐Modulated Glycopeptide Antibacterial Immunotherapy Against Osteomyelitis

Molecular chirality is a crucial determinant in drug design, as it often influences properties such as toxicity and stability. However, its role in regulating the interactions of peptide- and saccharide-based materials with pathogens and immune cells remains to be fully elucidated. In this study, we selectively designed a pair of glycopeptide isomers, L-FFK-β-D-Gal and D-FFK-β-D-Gal, as biomimetic antibiotics to study how molecular chirality affects antibacterial and immunomodulatory activity. Although the nanofibers formed by the two isomers have similar morphology, in vitro experiments show that the L-FFK-β-D-Gal assemblies showed stronger bactericidal activity to both Gram-positive bacteria and Gram-negative bacteria than their D-enantiomer counterparts. This enhanced antibacterial effect is mainly related to increased bacterial membrane permeability, impaired energy metabolism, signal transduction destruction, and L-enantiomer-induced amino acid biosynthesis inhibition. In vivo studies further show that these glycopeptide assemblies effectively reduce bone infections by directly eliminating bacteria and triggering chirality-dependent antibacterial immune responses. This chiral glycopeptide-based antibacterial immunotherapy pronouncedly enhances the antibacterial efficacy of biological materials, highlighting its potential for treating infectious osteomyelitis.