Penicillin-binding proteins 1, 2, and 3 (Staphylococcus aureus) and Penicillin-binding proteins (Streptococcus pneumoniae) (PBPs)

Penicillin-binding proteins (PBPs) are a group of membrane-associated enzymes essential for the biosynthesis of the bacterial cell wall (StatPearls, 2023). In Staphylococcus aureus, PBPs 1, 2, and 3 are vital for cell elongation, peptidoglycan cross-linking, and septum formation during division (UniProt, 2024). Similarly, in Streptococcus pneumoniae, multiple PBPs including 1a, 2x, and 2b are responsible for maintaining the structural integrity of the peptidoglycan layer (Zapun et al., 2008). These enzymes are the primary therapeutic targets for beta-lactam antibiotics, such as penicillins and cephalosporins (Bush & Bradford, 2016). The drugs function by mimicking the D-Ala-D-Ala substrate, covalently binding to the PBP active site and irreversibly inhibiting the transpeptidation reaction. This inhibition leads to a compromised cell wall, resulting in bacterial lysis and death. Resistance in these pathogens often involves the modification of PBPs or the acquisition of low-affinity variants like PBP2a, which necessitates the development of advanced antibiotics like ceftaroline.

Other names

DD-transpeptidasesPeptidoglycan transpeptidasesMurein hydrolasesPenicillin-binding proteins

Beta-lactam antibiotics target PBPs by acting as structural analogs of the D-alanyl-D-alanine terminus of peptidoglycan precursors. They covalently bind to the active site serine of the PBP transpeptidase domain, forming a stable acyl-enzyme complex that irreversibly inhibits the enzyme (StatPearls, 2023). This prevents the cross-linking of peptidoglycan chains, which is essential for bacterial cell wall stability, leading to cell wall weakening, osmotic rupture, and bacterial death (Bush & Bradford, 2016).