Unanticipated Quinoline Modification on Vancomycin as an Effective Strategy to Alter the Antibacterial Profile and Combat Multidrug Resistance

Lipid II, referred to as the bacterial "Achilles' heel" and serving as the target of vancomycin, remains inaccessible to vancomycin in Gram-negative bacteria due to their outer membrane (OM) barrier, rendering it intrinsically ineffective against these pathogens. Herein, we serendipitously discovered that a simple, single quinoline moiety modification on vancomycin yields quinovancins, which not only restore vancomycin susceptibility against acquired vancomycin-resistant strains but also unexpectedly expand its antibacterial spectrum to encompass certain Gram-negative Enterobacteriaceae (e.g., <i>Escherichia coli</i>, <i>Salmonella</i>) <i>in vitro</i> and <i>in vivo</i>. Intriguingly, substitution with a naphthalene group failed to confer such activity. Mechanistically, quinovancins overcome acquired resistance through augmented "cell wall-membrane" dual inhibitions in Gram-positive bacteria. In Gram-negative bacteria, the quinoline moiety functions as a shuttle, facilitating vancomycin's transit across the OM to the Lipid II site without compromising OM integrity─distinct from conventional OM-disrupting pathways. Besides, the best quinovancin candidate <b>3d</b> exhibits a synergistic sensitization effect to potentiate meropenem, particularly against carbapenem-resistant <i>E. coli</i>. Furthermore, <b>3d</b> demonstrates favorable druggability, including rapid and scalable synthesis, great solubility, outperformed <i>in vivo</i> pharmacokinetic profiles, and good safety. This work provides an unanticipated but promising strategy that enables the secondary development of vancomycin to combat bacterial multidrug resistance.