Peptidoglycan-Directed Chemical Ligation for Selective Inhibition on Gram-Positive Bacteria

[Image: see text] Microbicides with distinct antibacterial mechanisms show potential to combat multi-drug resistance bacteria. We herein report peptidoglycan-directed chemical ligation (PGCL) between alkyne-bearing vancomycin and an azide-tagged cationic polymer. The former binds peptidoglycan and inhibits peptidoglycan crosslinking, while the latter interferes the integrity of the bacterial membrane. PGCL results in enhanced bactericidal activity against Gram-positive Staphylococcus aureus (S. aureus) over Gram-negative Escherichia coli (E. coli). These data indicate the potential of PGCL to selectively and synergistically inhibit Gram-positive pathogens via dual modality antibacterial mechanisms of peptidoglycan-inhibiting antibiotics and bacterial membrane-disrupting polycations.