Penicillin-binding proteins 1b, 2, 4, 5, and 6 (Gram-negative bacteria) (PBPs (1b, 2, 4, 5, 6))

Penicillin-binding proteins (PBPs) 1b, 2, 4, 5, and 6 are a subset of enzymes essential for the synthesis and maintenance of the peptidoglycan layer in Gram-negative bacteria (UniProt: P02919). PBP1b is a high-molecular-weight (HMW) bifunctional enzyme responsible for both transglycosylation and transpeptidation, while PBP2 is an HMW transpeptidase critical for maintaining the rod shape of the cell (PubMed: 22210771). The low-molecular-weight (LMW) PBPs 4, 5, and 6 primarily function as DD-carboxypeptidases that regulate the degree of peptidoglycan cross-linking by removing terminal D-alanine residues from pentapeptide precursors (PubMed: 16428406). These proteins are the molecular targets for beta-lactam antibiotics, which act as substrate analogs and form a stable acyl-enzyme complex with the active-site serine, thereby inactivating the enzyme (StatPearls: NBK545311). The inhibition of these PBPs leads to the cessation of cell wall synthesis, triggering bacterial lysis and death. Resistance to antibiotics targeting these proteins often involves mutations that decrease drug affinity or the overproduction of LMW PBPs that can sequester the drugs (PubMed: 29445124). Understanding the specific roles of these PBPs is crucial for developing new antimicrobial agents that can bypass existing resistance mechanisms in Gram-negative pathogens.

Other names

DD-transpeptidasesDD-carboxypeptidasesPeptidoglycan biosynthetic enzymesMrcB (PBP1b)MrdA (PBP2)DacB (PBP4)DacA (PBP5)DacC (PBP6)

Irreversible inhibition of transpeptidase and carboxypeptidase activities by covalent binding to the active-site serine, preventing peptidoglycan cross-linking and leading to bacterial cell lysis.