The alarming growth of antibiotic-resistant superbugs such as new delhi metallo β-lactamase producing gram-negative bacteria (ndm-1 e. coli), vancomycin-resistant enterococci and staphylococci (vre, vrsa), methicillin-resistant s. aureus (mrsa) have become a major global health hazard. to address this issue, here we report the development of lipophilic cationic vancomycin analogues through simple synthetic methodology possessing excellent antibacterial activity against several drug-resistant bacterial strains (vre, vrsa, mrsa, e. coli, k. pneumoniae and a. baumanii). compared to known antibiotics such as vancomycin, efficacy greater than 1000-fold was demonstrated against vancomycin-resistant enterococci (vre). further, these compounds went on to display excellent efficacy against carbapenem-resistant gram-negative bacterial clinical isolates. new compound was shown to kill bacteria rapidly at low concentrations, and did not induce bacterial resistance. an optimized compound in the series, showed very high activity in methicillin-resistant staphylococcus aureus (mrsa) infected mouse model and vancomycin-resistant staphylococcus aureus (vrsa) infected mouse model, exhibited improved pharmacological properties and demonstrated superior antibacterial activity in whole blood. their impressive activity is credited to their additional mechanism of disrupting the bacterial cell membrane integrity (membrane depolarization, intracellular k+ ion leakage and membrane permeabilization) into vancomycin and opens up a great opportunity for the development of life saving antibiotics.