Penicillin-binding protein 2 (Neisseria gonorrhoeae) (PBP2)

Penicillin-binding protein 2 (PBP2) is an essential enzyme in the Gram-negative bacterium Neisseria gonorrhoeae that catalyzes the cross-linking of peptidoglycan strands during cell wall synthesis [1, 3]. It is a Class B penicillin-binding protein with transpeptidase activity, specifically involved in cell division and septum formation [16, 19]. PBP2 is the primary lethal target for beta-lactam antibiotics, such as penicillins and extended-spectrum cephalosporins like ceftriaxone [1, 10]. These drugs act by forming a stable covalent acyl-enzyme complex with the active site serine (Ser310), which inhibits the enzyme's ability to cross-link the cell wall, leading to bacterial lysis [3, 16]. Resistance to these antibiotics is primarily mediated by mutations in the penA gene, which encodes PBP2 [5, 13]. These mutations often result in mosaic alleles acquired through horizontal gene transfer, which significantly reduce the protein's affinity for antibiotics [10, 12]. Despite these structural changes, the mutated PBP2 must maintain sufficient transpeptidase activity to support bacterial growth [16, 18]. The emergence of ceftriaxone-resistant strains with highly remodeled PBP2 variants is a major global health concern, as it threatens the last effective first-line treatment for gonorrhea [10, 18]. New inhibitors, such as the experimental benzoxaborinine-based compound VNRX-14079, are being developed to target these resistant PBP2 variants [6, 7].

Other names

Peptidoglycan D,D-transpeptidase PenAPBP-2penAFtsI homolog

Inhibition of the transpeptidase activity by forming a covalent acyl-enzyme complex with the active site serine residue, which prevents the cross-linking of peptidoglycan strands and leads to bacterial cell death.