A Vancomycin-Arginine Conjugate Inhibits Growth of Carbapenem-resistant E. coli and Targets Cell-Wall Synthesis.

The emergence of multidrug-resistant Gram-negative bacteria, including carbapenem-resistant Enterobacteriaceae, is a major health problem that necessitates the development of new antibiotics. Vancomycin inhibits cell wall synthesis in Gram-positive bacteria, but is generally ineffective against Gram-negative bacteria and unable to penetrate the outer membrane barrier. In an effort to determine whether vancomycin and other antibiotics effective against Gram-positive bacteria could, through modification, be rendered effective against Gram-negative bacteria, we discovered that covalent attachment of a single arginine to vancomycin yielded conjugates with order-of-magnitude improvements in activity against Gram-negative bacteria, including pathogenic E. coli. The vancomycin-arginine conjugate (V-R) exhibited efficacy against actively-growing bacteria, induced loss of rod cellular morphology, and resulted in intracellular accumulation of peptidoglycan precursors, all consistent with cell-wall synthesis disrupt...