Penicillin-binding protein (singular form), specifically the D,D-transpeptidase activity (PBP)

Penicillin-binding proteins are a family of bacterial enzymes with essential roles in synthesizing and cross-linking peptidoglycan, which constitutes the rigid cell wall of most bacteria. Their principal activities are DD-transpeptidase (formation of peptide cross-links) and often DD-carboxypeptidase (trimming peptidoglycan). PBPs possess conserved motifs in their catalytic domains (SxxK, SxN, KTGT). Inhibition of PBPs by β-lactam antibiotics (e.g., penicillins, cephalosporins, carbapenems) prevents cell wall cross-linking, causing structural weaknesses that lead to bacterial cell death. Continued antibiotic pressure has led to clinically important resistance mechanisms involving PBP mutation or expression of alternative PBPs. PBPs are structurally related to β-lactamases and other proteases but possess distinctive active site features and mechanisms. This target is of central importance in antibacterial drug development and clinical microbiology, representing the canonical molecular target of the β-lactam class of antibiotics.

Other names

DD-transpeptidasePeptidoglycan D,D-transpeptidaseD-alanyl-D-alanine carboxypeptidase (for PBPs with both activities)TranspeptidasePBP (short for penicillin-binding protein)

β-lactam antibiotics bind covalently to the active site serine of PBPs/DD-transpeptidases, forming an acyl-enzyme complex and inactivating the enzyme irreversibly. This blocks cross-linking of peptidoglycan strands, leading to defective cell wall and bacterial death (bactericidal effect). Some non-β-lactam inhibitors mimic peptidoglycan structure to target DD-transpeptidases.