An acquired and a native penicillin-binding protein cooperate in building the cell wall of drug-resistant staphylococci

The blanket resistance of methicillin-resistant Staphylococcus aureus to al l beta -lactam antibiotics-which had such a devastating impact on chemother apy of staphylococcal infections-is related to the properties of the key co mponent of this resistance mechanism: the "acquired" penicillin-binding pro tein (PBP)-2A, which has unusual low affinity for all beta -lactam antibiot ics. Until now, the accepted model of resistance implied that in the presen ce of beta -lactam antibiotics in the surrounding medium, PBP2A must take o ver the biosynthesis of staphylococcal cell wall from the four native staph ylococcal PBPs because the latter become rapidly acylated and inactivated a t even low concentrations of the antibiotic. However, recent observations i ndicate that this model requires revision. Inactivation of the transglycosy lase domain, but not the transpeptidase domain, of PBP2 of S. aureus preven ts expression of beta -lactam resistance, despite the presence of the low-a ffinity PBP2A. The observations suggest that cell-wall synthesis in the pre sence of beta -lactam antibiotics requires the cooperative functioning of t he transglycosylase domain of the native staphylococcal PBP2 and the transp eptidase domain of the PBP2A, a protein imported by S. aureus from an extra species source.