Methicillin-resistant Staphylococcus aureus (MRSA) strains pose major treatment challenges due to their innate resistance to most β-lactams under standard in vitro antimicrobial susceptibility testing conditions. A novel phenotype among MRSA, termed "NaHCO₃ responsiveness," where certain strains display increased susceptibility to β-lactams in the presence of NaHCO₃, has been identified among a relatively large proportion of MRSA isolates. One underlying mechanism of NaHCO₃ responsiveness appears to be related to decreased expression and altered functionality of several genes and proteins involved in cell wall synthesis and maturation. Here, we studied the impact of NaHCO₃ on wall teichoic acid (WTA) synthesis, a process intimately linked to peptidoglycan (PG) synthesis and functionality, in NaHCO₃-responsive versus -nonresponsive MRSA isolates. NaHCO₃ sensitized responsive MRSA strains to cefuroxime, a specific penicillin-binding protein 2 (PBP2)-inhibitory β-lactam known to synergize with early WTA synthesis inhibitors (e.g., ticlopidine). Combining cefuroxime with ticlopidine with or without NaHCO₃ suggested that these latter two agents target the same step in WTA synthesis. Further, NaHCO₃ decreased the abundance and molecular weight of WTA only in responsive strains. Additionally, NaHCO₃ stimulated increased autolysis and aberrant cell division in responsive strains, two phenotypes associated with disruption of WTA synthesis. Of note, studies of key genes involved in the WTA biosynthetic pathway (e.g., tarO, tarG, dltA, and fmtA) indicated that the inhibitory impact of NaHCO₃ on WTA biosynthesis in responsive strains likely occurred posttranslationally. IMPORTANCE MRSA is generally viewed as resistant to standard β-lactam antibiotics. However, a NaHCO₃-responsive phenotype is observed in a substantial proportion of clinical MRSA strains in vitro, i.e., isolates which demonstrate enhanced susceptibility to standard β-lactam antibiotics (e.g., oxacillin) in the presence of NaHCO₃. This phenotype correlates with increased MRSA clearance in vivo by standard β-lactam antibiotics, suggesting that patients with infections caused by such MRSA strains might be amenable to treatment with β-lactams. The mechanism(s) behind this phenotype is not fully understood but appears to involve mecA-PBP2a production and maturation axes. Our study adds significantly to this body of knowledge in terms of additional mechanistic targets of NaHCO₃ in selected MRSA strains. This investigation demonstrates that NaHCO₃ has direct impacts on S. aureus wall teichoic acid biosynthesis in NaHCO₃-responsive MRSA. These findings provide an additional target for new agents being designed to synergistically kill MRSA using β-lactam antibiotics.

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