Penicillin-binding proteins 1 and 3 (PBP1 and PBP3) (PBP1/3)

Penicillin-binding proteins 1 and 3 (PBP1 and PBP3) are essential membrane-anchored enzymes in bacteria that play critical roles in the assembly and maintenance of the peptidoglycan cell wall (rcsb.org, wikipedia.org). PBP1, which includes the major isoforms PBP1a and PBP1b, is a bifunctional enzyme possessing both glycosyltransferase activity for glycan chain elongation and transpeptidase activity for peptide cross-linking (nih.gov, rcsb.org). In contrast, PBP3 is a class B transpeptidase primarily localized to the division septum, where it is indispensable for the process of septation; its inhibition results in the formation of long, non-dividing bacterial filaments (nih.gov, wikipedia.org). These proteins serve as the primary therapeutic targets for the beta-lactam class of antibiotics, including penicillins, cephalosporins, and carbapenems (rcsb.org, nih.gov). The drugs act as structural analogs of the D-alanyl-D-alanine substrate, covalently binding to the active site serine and irreversibly inactivating the enzyme (nih.gov, oup.com). Clinical resistance often arises through mutations in the genes encoding these PBPs, such as ponA and ftsI, which reduce the binding affinity of the antibiotics while maintaining enough enzymatic function for bacterial survival (nih.gov).

Other names

PBP1PBP3PBP1aPBP1bftsIponAponBmrcAmrcBpbpC

Covalent inhibition of the transpeptidase domain by forming a stable acyl-enzyme complex with the active site serine, which prevents the cross-linking of peptidoglycan strands and leads to cell wall instability and bacterial lysis.