Penicillin-binding protein (DD-transpeptidase) (PBP)

Penicillin-binding proteins (PBPs) are a group of essential bacterial enzymes, primarily DD-transpeptidases, that catalyze the final cross-linking step of peptidoglycan biosynthesis in the bacterial cell wall (Wikipedia, 2024). By forming peptide bonds between adjacent glycan strands, PBPs maintain the structural integrity and osmotic stability required for bacterial survival and division (FEMS Microbiology Reviews, 2008). These enzymes are the primary targets for beta-lactam antibiotics, including penicillins, cephalosporins, and carbapenems, which mimic the enzyme's natural substrate to form an irreversible covalent bond with the active site (MDPI, 2015). This inhibition halts cell wall construction, leading to bacterial lysis and death. Because PBPs are unique to prokaryotes and absent in human cells, they are ideal targets for selective toxicity. However, the clinical utility of targeting PBPs is increasingly challenged by the emergence of resistance mechanisms, such as the acquisition of low-affinity PBP variants like PBP2a in MRSA or mutations in native PBP genes (Oxford Academic, 2016). Understanding PBP dynamics is crucial for developing next-generation antibiotics that can overcome these resistance patterns (PMC, 2016).

Other names

DD-peptidaseD-alanyl-D-alanine carboxypeptidaseDD-transpeptidaseBacterial cell wall transpeptidasePBP

Beta-lactam antibiotics act as structural analogs of the D-alanyl-D-alanine terminus of peptidoglycan precursors. They covalently bind to the active-site serine residue of the DD-transpeptidase domain of PBPs, forming a stable acyl-enzyme intermediate. This irreversible inhibition prevents the cross-linking of peptidoglycan strands, leading to a weakened cell wall, osmotic instability, and eventual bacterial cell lysis (Wikipedia, 2024; FEMS Microbiology Reviews, 2008).