2019/09/03 by Alexandra Antonoplis, Xiaoyu Zang, Tristan Wegner +2 · 1 citation
Biochemistry, Genetics and Molecular Biology · Environmental Science · Immunology and Microbiology · #Antibiotic Resistance in Bacteria #Bacteriophages and microbial interactions #Antimicrobial Peptides and Activities
paper · doi:10.1021/acschembio.9b00565
openalex publication_date 2019/09/03 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
The emergence of multi-drug-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 is 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 the 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 the loss of rod cellular morphology, and resulted in the intracellular accumulation of peptidoglycan precursors, all consistent with cell-wall synthesis disruption as its mechanism of action. Membrane permeabilization studies demonstrated an enhanced outer membrane permeability of V–R as compared with vancomycin. The conjugate exhibited no mammalian cell toxicity or hemolytic activity in MTT and hemolysis assays. Our study introduces a new vancomycin derivative effective against Gram-negative bacteria and underscores the broader potential of generating new antibiotics through combined mode-of-action and synthesis-informed design studies.