Penicillin-binding protein 2a (Streptococcus pneumoniae) (PBP2a)

Penicillin-binding protein 2a (PBP2a) from Streptococcus pneumoniae is a high-molecular-weight Class A penicillin-binding protein that plays a dual role in bacterial cell wall biosynthesis (UniProt P0A4G2). It possesses both a glycosyltransferase (transglycosylase) domain, which polymerizes glycan chains, and a transpeptidase domain, which cross-links these chains via peptide bridges (Contreras-Martel et al., 2006). The transglycosylase domain specifically catalyzes the formation of beta-1,4-glycosidic bonds between N-acetylglucosamine and N-acetylmuramic acid subunits of the peptidoglycan layer. Because this domain is essential for bacterial survival and lacks a human homolog, it is a highly attractive target for antimicrobial drug development (Zapun et al., 2008). While most clinical antibiotics target the transpeptidase activity, inhibitors of the transglycosylase domain, such as moenomycin, offer a way to bypass certain beta-lactam resistance mechanisms. However, the development of clinically viable transglycosylase inhibitors remains a challenge due to the complex nature of the substrate-binding site and the hydrophobic properties of known inhibitors (Di Guilmi et al., 2003).

Other names

PBP-2aBifunctional penicillin-binding protein 2aClass A PBP2apbp2A

Inhibition of the transglycosylase domain prevents the polymerization of Lipid II into glycan strands, halting peptidoglycan backbone formation.