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A Pilum of Staphylococcus Aureus is the most common form of penicillin-resistant Staphylococcus aureus (MRSA) in humans, causing illnesses from minor skin and soft tissue infections to life-threatening pneumonia, sepsis, and septic shock. MRSA resistance to penicillin is caused by a PBP2a penicillin-binding protein (PBP) with low affinity for beta-lactam antibiotics, including penicillin. This study elucidates the contribution of PBP2a to the susceptibility of S. aureus to cephalosporins, as well as the ability of the low-affinity cephalosporin-specific PBP, PBP2', to rescue S. aureus from treatment with beta-lactam antibiotics. Mutations in the PBP2a coding sequence in S. aureus prevented the susceptibility to cefoxitin and cefazolin, and the ability of the cell to restore antibiotic susceptibility upon disruption of pbp2a. An affinity-purified PBP2a complemented the resistance of a PBP2a-deficient S. aureus to beta-lactam antibiotics, including cefoxitin, and loaded with antibiotics. The results indicated that PBP2a is a low-affinity penicillin-binding protein that contributes to the resistance of MRSA to cefoxitin and cefazolin, and that the high-affinity PBP2' contributes to the ability of S. aureus to restore these levels of beta-lactam antibiotics.
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