An Achilles' heel for methicillin-resistant Staphylococcus aureus? Re-evaluating β-lactam susceptibility of MRSA

Methicillin-resistant Staphylococcus aureus (MRSA) infections (i.e., carrying the mec gene) are challenging to treat due to their inherent resistance to most antistaphylococcal β-lactams. Given the poor outcome of severe MRSA infections and limitations of the current approved treatments, there is growing interest in repurposing β-lactams as part of a treatment strategy for these infections. Here, we review the current literature on β-lactam susceptibility phenotypes in MRSA. We describe four phenotypes: oxacillin-susceptible, sensitivity to combinations of β-lactam-β-lactamase inhibitors, NaHCO₃ responsiveness, and synergy between classes of β-lactams that target different penicillin-binding proteins. For each phenotype, we discuss the genetic background, known explanatory biological mechanisms, and associations between MRSA β-lactam susceptibility phenotype and treatment response to β-lactam therapy.