Penicillin-binding protein 2 and 3 (PBP2/3)

Penicillin-binding proteins (PBPs) are essential bacterial enzymes anchored in the cytoplasmic membrane that catalyze the final stages of peptidoglycan synthesis, the structural backbone of the bacterial cell wall. In Gram-negative bacteria, PBP2 (MrdA) and PBP3 (FtsI) are high-molecular-weight transpeptidases with distinct and vital roles in cell morphology and viability. PBP2 is primarily responsible for maintaining the rod shape of the bacteria by directing lateral wall elongation, and its specific inhibition by drugs like mecillinam results in the formation of spherical cells. PBP3 is essential for the formation of the division septum during binary fission; its inhibition, notably by monobactams like aztreonam, leads to the formation of long, non-dividing filaments. These proteins are the primary targets for beta-lactam antibiotics, which bind covalently to the active-site serine residue, thereby halting cell wall cross-linking and triggering autolytic pathways. Resistance to these agents often involves the acquisition of beta-lactamases or structural modifications in the PBPs that reduce drug affinity, particularly in pathogens like Pseudomonas aeruginosa and Acinetobacter baumannii.

Other names

PBP2PBP3FtsIMrdAPeptidoglycan glycosyltransferaseD-alanyl-D-alanine carboxypeptidaseTranspeptidaseSeptum-forming PBPElongation-specific PBP

Covalent inhibition of the transpeptidase domain by acting as a structural analog of the D-alanyl-D-alanine substrate, preventing peptidoglycan cross-linking and leading to bacterial cell lysis.