Structure, biochemistry and mechanism of action of glycopeptide antibiotics

Abstract

Glycopeptide antibiotics, including vancomycin and teicoplanin, are large, rigid molecules that inhibit a late stage in bacterial cell wall peptidoglycan synthesis. The three-dimensional structure contains a cleft into which peptides of highly specific configuration (L-aa-D-aa-D-aa) can fit: such sequences are found only in bacterial cell walls, hence glycopeptides are selectively toxic. Glycopeptides interact with peptides of this conformation by hydrogen bonding, forming stable complexes. As a result of binding to L-aa-D-Ala-D-Ala groups in wall intermediates, glycopeptides inhibit, apparently by steric hindrance, the formation of the backbone glycan chains (catalysed by peptidoglycan polymerase) from the simple wall subunits as they are extruded through the cytoplasmic membrane. The subsequent transpeptidation reaction that imparts rigidity to the cell wall is also thus inhibited. This unique mechanism of action, involving binding of the bulky inhibitor to the substrate outside the membrane so that the active sites of two enzymes cannot align themselves correctly, renders the acquisition of resistance to the glycopeptide antibiotics more difficult than that to the majority of the other antibiotic groups.

Targeting Antibiotic Resistance

“…Glycopeptides all share a common mode of action, which consists of binding to the C‐terminal d ‐alanyl‐ d ‐alanine of peptidoglycan precursors 125. This was first discovered in vancomycin in the late 1960s and then confirmed by NMR studies by the Williams group in 1983 126.…”

“…The resulting steric hindrance from this binding inhibits the transglycosylation and transpeptidation steps in cell wall synthesis ultimately resulting in bacterial cell death (Figure 26). 125 …”

Antibacterial activities and modes of action of vancomycin and related glycopeptides

“…The transglycosylase enzyme that transfers the disaccharide of the peptidoglycan precursor to the growing glycan polymer of the cell wall peptidoglycan is inhibited (1, 2), presumably due to the steric bulkiness of the glycopeptidepeptidoglycan precursor (31). Furthermore, even if some glycan chain synthesis occurred, since the acyl-D-ala-D-ala portion of the peptidoglycan precursor is enveloped by the larger glycopeptide, the transpeptidase enzyme reaction is probably inhibited (31).…”

“…Furthermore, even if some glycan chain synthesis occurred, since the acyl-D-ala-D-ala portion of the peptidoglycan precursor is enveloped by the larger glycopeptide, the transpeptidase enzyme reaction is probably inhibited (31). It seems that both the transglycosylase and transpeptidase enzyme reactions that complete the synthesis of the rigid cell wall peptidoglycan may be inhibited by the glycopeptides.…”

Lipoglycopeptide Antibacterial Agents in Gram-Positive Infections: A Comparative Review

“…2). Via their aglycone moiety, they establish five hydrogen bounds with the D-Ala-D-Ala termini of pentapeptidic precursors, which by steric hindrance prevents the transglycosylation reaction leading to the extension of the glycan backbone of peptidoglycan as well as the transpeptidation reaction leading to the crosslinking of pentapeptide bridges [17,18]. This mode of action confers a slowly bactericidal character to vancomycin, which is limited to fast-growing organisms [19].…”