Like many antibiotics (including the penicillins), vancomycin acts by interfering with the construction of cell walls in bacteria. Cell wall biosynthesis is one of the major means of killing bacteria.
The Bacterial Cell Wall. Bacterial cells are surrounded by a cell wall that is composed of a mesh-like network called peptidoglycan. The cell wall is absolutely crucial to the survival of the bacterium, for it provides the entire cell with mechanical support. The cell faces a huge intracellular osmotic pressure, and the rigidity of the peptidoglycan helps to maintain the cell’s shape and prevent it from lysing (exploding). Inhibition of the biosynthetic pathway of the peptidoglycan layer in bacteria will therefore cause the cell to lyse.
The peptidoglycan layer is composed of a linear polysaccharide chain composed of alternating residues of the carbohydrates N-acetyl glucosamine (GlcNAc) and N-acetyl muramic acid (MurNAc). Many of these chains run parallel to one another, and are connected with each other via a peptide moiety of the five amino acids L-Alanine-D-Glutamic acid-L-Lysine-D-Ala-D-Ala. The peptide cross-bridges connect the MurNAc residues on the glycan chains, resulting in a net-like structure. This meshwork that forms the bacterial cell wall imparts a great deal of structural support to the cell.
The bacterial peptidoglycan is synthesized in a series of steps that take place both inside and outside of the cell membrane. Just outside the membrane lie the transglycosylases, enzymes that put together GlcNAc-MurNAc subunits to form the glycan chains, and the transpeptidases, which perform the peptide cross-linking between these chains. The vancomycin family of antibiotics inhibits this stage of cell wall synthesis. While penicillin affects the active sites of the transpeptidase enzymes themselves, vancomycin binds to the peptide substrate and prevents it from binding to the enzyme’s active site. The bottom surface of vancomycin makes five hydrogen bonds to the D-Ala-D-Ala amino acids at the end of the peptide cross-bridges. By binding to these residues with high affinity, the antibiotic prevents them from being accessible to the active site of the transpeptidases. Peptide cross-linking therefore cannot occur, and the structural integrity of the peptidoglycan is compromised, causing the cell to lyse.