MRSA (Methicillin-Resistant S. aureus) is becoming an increasingly problematic organism, frequently associated with recurrences and relapses. This has been ascribed to antibacterial resistance and survival within eukaryotic cells. In the course of systematic studies evaluating the activity of b-lactams, we observed that MRSA becomes susceptible to b-lactams in the intracellular milieu or when the bacteria are exposed to pH <= 5.5. This influence of acidic pH was first ascribed to a diminished copy numbers of PBP2a (Hartman and Tomasz, 1984), a unique transpeptidase poorly inhibited by b-lactams (because of a closed conformation of its active site). However, we showed that growing bacteria at acidic pH improves significantly the binding of b-lactams towards MRSA (Lemaire et al, AAC, 2007). Concentrating our effort on a purified PBP2a, we showed that, at acidic pH, PBP2a binds more avidly b-lactams and undergoes a conformational change in the presence of b-lactam (which is a crucial step for the opening of the active site) (Lemaire et al, JBC, 2008). In terms of mechanistic consequences, these variations were quite similar than those recently reported for ceftobiprole (a novel anti-MRSA cephalosporin inhibiting more efficiently PBP2a). Therefore, these observations argue that PBP2a is most likely evolved for its physiological function at pH 7.0 owing to its closed conformation, which is not maintained at acidic pH.