Chiral peptidoglycan mimics target bacterial wall biosynthesis for pathogen intervention

The global burden of microbial infections and antimicrobial resistance, coupled with the absence of precise bacterial recognition modalities, demands innovative breakthroughs in antibacterial treatment. Here, we report a chirality-specific biomimic—D-alanine-conjugated peptidoglycan mimics (D-PM)—designed for bacterial recognition. D-PM exhibits broad-spectrum, effective recognition across ESKAPE pathogens, antibiotic-resistant strains, and clinical isolates, while displaying minimal interaction with eukaryotic cells. We elucidate the bacterial recognition mechanism, wherein D-PM—act as a biosynthetic substrates—become incorporated into peptidoglycan biosynthesis. This reveals a mechanism by which macromolecular mimetics are assimilated into bacterial biosynthesis, providing insights into bacterial recognition. Beyond recognition, D-PM enables the construction of pathogen-specific imaging agents and antibiotic-targeted delivery systems. In localized and systemic infection models, D-PM achieves efficient pathogen localization, tissue penetration, and enhanced therapeutic outcomes. This work presents a molecularly engineered strategy for bacterial recognition and intervention, offering a translational approach to address the escalating threat of infectious diseases. Improved delivery of antibiotics is needed. Here, the authors report on chirality-specific peptidoglycan mimics that hijack bacterial cell wall synthesis, enabling pathogen recognition, bioimaging, and targeted antibiotic delivery while minimizing off-target effects on host cells.