Antibiotic-resistant superbugs such as vancomycin-resistant Enterococci (VRE) and Staphylococci have become a major global health hazard. To address this issue, we synthesized vancomycin aglycon dimers to systematically probe the impact of a linker on biological activity. A dimer having a pendant lipophilic moiety in the linker showed ∼300-fold more activity than vancomycin against VRE. The high activity of the compound is attributed to its enhanced binding affinity to target peptides which resulted in improved peptidoglycan (cell wall) biosynthesis inhibition. Therefore, our studies suggest that these compounds, prepared by using facile synthetic methodology, can be used to combat vancomycin-resistant bacterial infections.