The ability to resist the effect of a wide range of antibiotics makes methicillin-resistant
Staphylococcus aureus (MRSA) a leading global human pathogen. A key determinant of resistance to
β-lactam antibiotics in this organism is penicillin-binding protein 2a (PBP2a), an enzyme that catalyzes
the crosslinking reaction between two adjacent peptide stems during the peptidoglycan biosynthesis.
The recently published crystal structure of the complex of PBP2a with ceftaroline, a cephalosporin
antibiotic that shows efficacy against MRSA, has revealed the allosteric site at 60-Å distance
from the transpeptidase domain. Binding of ceftaroline to the allosteric site of PBP2a triggers conformational changes that
lead to the opening of the active site from a closed conformation, where a second molecule of ceftaroline binds to give inhibition
of the enzyme. The discovery of allostery in MRSA remains the only known example of such regulation of cellwall
biosynthesis and represents a new paradigm in fighting MRSA. This review summarizes the present knowledge of
the allosteric mechanism, the conformational changes allowing PBP2a catalysis and the means by which some clinical
strains have acquired resistance to ceftaroline by disrupting the allosteric mechanism.
Keywords: Allosteric mechanism, antibiotic resistance, β-lactam antibiotics, conformational change, methicillin-resistant
Staphylococcus aureus, penicillin-binding proteins, X-ray crystallography.
Rights & PermissionsPrintExport