Exposing a chink in the armor of methicillin-resistant Staphylococcus aureus.

A ntibiotics have provided arguably the greatest benefit to human health among developments of the past century, and so the emergence of widespread antibiotic resistance is now a grave threat to 21stcentury health (1). Among antibioticresistant organisms, methicillin-resistant Staphylococcus aureus (MRSA) emerged early and presents one of the most serious challenges, a situation compounded by the extension of its range from being primarily a nosocomial problem to include community-acquired and livestock-associated spread (2, 3). Novel strategies to combat MRSA are therefore urgently needed, and so it is notable that, in PNAS, Brown et al. (4) have identified a surprising chink in the bacterial armor that may allow the development of novel therapeutic strategies to target MRSA. β-Lactam antibiotics such as methicillin target the penicillin-binding proteins that form the peptide cross-links that provide structural integrity to the peptidoglycan, the uniquely bacterial polymer of the cell wall. MRSA strains emerge when methicillin-susceptible S. aureus (MSSA) acquires the mecA gene through lateral gene transfer on the staphylococcal chromosomal cassettemecA, which encodes a lowaffinity penicillin-binding protein, PBP2a, which is insensitive to penicillin and to many other β-lactam antibiotic agents (3, 5). However, the robustness of the MRSA phenotype is modulated by many other aspects of the MSSA strain background that acquires mecA (6). The complexity of the MRSA phenotype thus offers hope that drug interactions and other interventions can be devised that will allow the restoration of an MSSA phenotype to MRSA strains (7–9). The work of Brown et al. (4) identifies a significant target that may be exploited to allow resensitization of MRSA.