Penicillin-binding proteins 1-3 (PBP1-3)

Penicillin-binding proteins (PBPs) 1, 2, and 3 are a group of essential bacterial enzymes that catalyze the final steps of peptidoglycan biosynthesis, the structural backbone of the bacterial cell wall (StatPearls, 2023). PBP1 (often existing as isoforms 1a and 1b) is a bifunctional enzyme with transglycosylase and transpeptidase activities responsible for cell wall elongation, while PBP2 and PBP3 are transpeptidases primarily involved in maintaining rod shape and forming the division septum, respectively (UniProt, 2024). These proteins are the primary therapeutic targets for beta-lactam antibiotics, such as penicillins, cephalosporins, and carbapenems (PubMed, 2021). When these drugs bind covalently to the active site of PBPs, they inhibit the cross-linking of peptidoglycan strands, leading to structural instability and osmotic lysis of the bacterium (Nature Reviews Microbiology, 2015). Resistance to these agents frequently involves mutations in the PBP genes or the acquisition of exogenous PBPs with low affinity for beta-lactams, which is a major challenge in treating clinical infections (NIH, 2022).

Other names

PBPsPeptidoglycan synthasesDD-transpeptidasesD-alanyl-D-alanine carboxypeptidasesMurein synthases

Beta-lactam antibiotics act as structural analogs of the D-alanyl-D-alanine terminus of peptidoglycan precursors. They bind covalently to the active-site serine residue of penicillin-binding proteins 1-3, irreversibly inhibiting the transpeptidation reaction. This blockade prevents the cross-linking of peptidoglycan chains, resulting in a compromised cell wall that cannot withstand osmotic pressure, leading to bacterial cell death.