A C-terminus modification to a binding pocket-modified vancomycin introduces a quaternary ammonium salt that provides a binding pocket-modified vancomycin analog with a second mechanism of action that is independent of D-Ala-D-Ala/D-Ala-D-Lac binding. The modification disrupts cell wall integrity and induces cell wall permeability complementary to the glycopeptide inhibition of cell wall synthesis, and provides synergistic improvements in antimicrobial potency (200-fold) against vancomycin-resistant bacteria. Combining the C- terminus and binding pocket modifications with an orthogonal (4-chlorobiphenyl ) methyl addition to the vancomycin disaccharide provides even more potent antimicrobial agents whose activity can be attributed to three independent and synergistic mechanisms of action, only one of which requires D-Ala-D-Ala/D-Ala- D-Lac binding. The resulting modified vancomycins display little propensity for acquired resistance through serial exposure of vancomycin-resistant Enterococci and their durability against such challenges as well as their antimicrobial potency follow predicable trends. Methods of treatment with and compositions containing the modified vancomycins are disclosed.