Methicillin-resistant Staphylococcus aureus (MRSA) acquires high-level resistance against β-lactam antibiotics by expressing penicillin-binding protein 2a (PBP2a). PBP2a is a cell wall-synthesizing protein whose closed active site exhibits a reduced binding affinity toward β-lactam antibiotics. Ceftaroline (CFT), a fifth-generation cephalosporin, can effectively inhibit the PBP2a activity by binding to an allosteric site to trigger the active site opening, allowing a second CFT to access the active site. However, the essential mechanism behind the allosteric behavior of PBP2a remains unclear. Herein, computational simulations are employed to elucidate how CFT allosterically regulates the conformation and dynamics of the active site of PBP2a. While CFT stabilizes the allosteric domain surrounding it, it simultaneously enhances the dynamics of the catalytic domain. Specifically, the study successfully captured the opening process of the active pocket in the allosteric CFT-bound systems and discovered that CFT alters the potential signal-propagating pathways from the allosteric site to the active site. These findings reveal the implied mechanism of the CFT-mediated allostery in PBP2a and provide new insights into dual-site drug design or combination therapy against MRSA targeting PBP2a.
Keywords: MRSA; allosteric regulation; ceftaroline; molecular dynamics simulation; penicillin-binding protein 2a; β-lactams.