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Review
, 66 (8), 572-7

Penicillin-binding Protein 2a of Methicillin-Resistant Staphylococcus Aureus

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Review

Penicillin-binding Protein 2a of Methicillin-Resistant Staphylococcus Aureus

Jennifer Fishovitz et al. IUBMB Life.

Abstract

High-level resistance to β-lactam antibiotics in methicillin-resistant Staphylococcus aureus (MRSA) is due to expression of penicillin-binding protein 2a (PBP2a), a transpeptidase that catalyzes cell-wall crosslinking in the face of the challenge by β-lactam antibiotics. The activity of this protein is regulated by allostery at a site 60 Å distant from the active site, where crosslinking of cell wall takes place. This review discusses the state of knowledge on this important enzyme of cell-wall biosynthesis in MRSA.

Keywords: allosteric regulation; conformational change; methicillin-resistant Staphylococcus aureus; resistance mechanism; β-lactam antibiotics.

Figures

Figure 1
Figure 1
The core structures of penicillins, cephalosporins, and carbapenems mimic the d-Ala-d-Ala of the peptide stem of the cell wall.
Figure 2
Figure 2
Crosslinking of peptidoglycan strands in cell-wall synthesis. Elongation of the glycan strand is carried out by PBPs with transglycosylase activity. The transpeptidation reaction, where the terminal d-Ala is displaced and the peptide stems are crosslinked is accomplished by PBPs such as PBP2a in MRSA.
Figure 3
Figure 3
The minimal scheme for interactions of PBP2a with β-lactam antibiotics. The β-lactam interacts reversibly with the free enzyme before forming the stable acyl-enzyme species (E–I). Deacylation is slow (k3) and the reaction is essentially irreversible.
Figure 4
Figure 4
X-ray structures of PBP2a in A. the apo-enzyme form (PDB code 1VQQ) B. complex with ceftaroline bound at the active site and allosteric site (3ZG0) C. complex of PBP2a with ceftobiprole acylating the active site (4DKI). The side chains of Y446 and M641, which act as gatekeepers of the active site, are shown as black sticks (1 o’clock). D. Chemical structures of ceftobiprole and ceftaroline. The R1 and R2 groups are shown in blue and red, respectively.

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