Penicillin-binding protein 4 and 5 (PBP4/5)

Penicillin-binding proteins (PBPs) are essential membrane-associated enzymes that catalyze the final steps of peptidoglycan biosynthesis, which is critical for maintaining the structural integrity of the bacterial cell wall (Source: Wikipedia, NIH.gov). In Gram-positive bacteria, low-affinity PBPs such as PBP4 and PBP5 are key mediators of resistance to beta-lactam antibiotics (Source: OSTI.gov). PBP5 is the primary determinant of ampicillin resistance in Enterococcus faecium, while PBP4 has been increasingly recognized for its role in high-level beta-lactam resistance in Staphylococcus aureus and Enterococcus faecalis (Source: NIH.gov). These proteins function as transpeptidases or carboxypeptidases, facilitating the cross-linking of peptidoglycan chains (Source: ResearchGate). Beta-lactam drugs, including penicillins and advanced-generation cephalosporins like ceftaroline, target these enzymes by covalently binding to their active-site serine, thereby inhibiting cell wall synthesis and leading to bacterial death (Source: MDPI, NIH.gov). However, mutations or overexpression of these low-affinity PBPs allow bacteria to continue cell wall assembly even in the presence of antibiotics, posing a significant challenge in treating clinical infections (Source: NIH.gov).

Other names

D-alanyl-D-alanine carboxypeptidaseDD-transpeptidaseLow-affinity penicillin-binding proteinspbpFdacBPenicillin-binding protein 2a (PBP2a)Penicillin-binding protein 2x (PBP2x)

Beta-lactam antibiotics act as substrate analogs of the D-Ala-D-Ala terminus of peptidoglycan precursors, covalently binding to the active-site serine of PBPs (Source: NIH.gov). This inhibition prevents the transpeptidation and carboxypeptidation reactions necessary for peptidoglycan cross-linking, leading to cell wall instability and bacterial lysis (Source: Wikipedia).