Quinoline tag helps vancomycin breach gram-negative defenses

Vancomycin is a common antibiotic used to treat gram-positive bacterial infections. It targets a key building block of the bacterial cell wall called Lipid II, but it can’t reach this lipid in gram-negative pathogens because their outer membranes block such large molecules. Now, chemists at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences have found that attaching a small quinoline group to vancomycin lets it slip inside the bacteria and reach its target (J. Am. Chem. Soc. 2025, DOI: 10.1021/jacs.5c14268).“It’s genuinely surprising that the add-on gives vancomycin any ability at all to hit gram negatives,” says Kim Lewis, an antibiotic researcher at Northeastern University who was not involved in the study.Previously, chemists had tried attaching cationic groups, transport peptides, or hydrophobic anchors to vancomycin—methods that increase the permeability of the outer membrane but are only modestly effective at pushing the drug inside. Unlike those approaches, the quinoline tweak appears to work without forcing open the membrane; it’s a gentler route that may reduce toxicity and make resistance harder to evolve.While the team originally added the quinoline to boost vancomycin’s activity against resistant gram-positive bacteria, several of the modified molecules unexpectedly killed the multidrug-resistant gram-negatives Escherichia coli and Salmonella. They also worked better against stubborn gram-positive superbugs like methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci.“We were stunned by how robust the gram-negative activity was,” says Dongliang Guan, a medicinal chemist and the study’s senior author. He notes that treated cells piled up unused cell-wall building blocks—the same pattern seen