Bifunctional Penicillin-Binding Proteins (PBPs) catalyze bacterial peptidoglycan synthesis; their glycosyltransferase (GT) activity carries out glycan chain polymerization and the transpeptidase domain allows stem peptide crosslinking. The latter domain is the target of β-lactam antibiotics, while the glycosyltransfer region is a potential target for the design of novel antibacterial drugs. This review aims at presenting recent advances related to various aspects of bifunctional PBPs. The coordinated activity between the different PBPs and the peptidoglycan hydrolases has been investigated by genetic and immunofluorescence localization approaches, and the results offer insight onto the cellular functionalities of these essential enzymes. Deletions of all bifunctional PBPs in two Gram-positive organisms did not cause cell death, suggesting the presence of a yet unidentified protein competent for the polymerization of the glycan chains in the absence of the classical GT domain of the PBPs. An important milestone in the study of the GT functionality has been the chemical and enzymatic synthesis of the natural lipid II substrate. This molecule has been employed in detailed study of the GT activity of bifunctional Escherichia coli PBP1b and PBP2a from Streptococcus pneumoniae. Mapping of the interaction between GT domains and inhibitors (moenomycin, vancomycin) and between lipid II and various peptide antibiotics (nisin, mersacidin, ramoplanin) may be useful in the design of new efficient drugs inhibiting peptidoglycan biosynthesis.
Keywords: penicillin-binding proteins, glycosyltransferase activity, lipid II, moenomycin, vancomycin, antibiotic resistance
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