ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) strains are a major challenge for clinicians due, in part, to their resistance to most β-lactams, the first-line treatment for methicillin-susceptible S. aureus . A phenotype termed “NaHCO ₃ -responsiveness” has been identified, wherein many clinical MRSA isolates are rendered susceptible to standard-of-care β-lactams in the presence of physiologically relevant concentrations of NaHCO ₃ , in vitro and ex vivo ; moreover, such “NaHCO ₃ -responsive” isolates can be effectively cleared by β-lactams from target tissues in experimental infective endocarditis (IE). One mechanistic impact of NaHCO ₃ exposure on NaHCO ₃ -responsive MRSA is to repress WTA synthesis. This NaHCO ₃ effect mimics the phenotype of tarO -deficient MRSA, including sensitization to the PBP2-targeting β-lactam, cefuroxime (CFX). Herein, we further investigated the impacts of NaHCO ₃ exposure on CFX susceptibility in the presence and absence of a WTA synthesis inhibitor, ticlopidine (TCP), in a collection of clinical MRSA isolates from skin and soft tissue infections (SSTI) and bloodstream infections (BSI). NaHCO ₃ and/or TCP enhanced susceptibility to CFX in vitro , by both minimum inhibitor concentration (MIC) and time-kill assays, as well as in an ex vivo simulated endocarditis vegetations (SEV) model, in NaHCO ₃ -responsive MRSA. Furthermore, in experimental IE (presumably in the presence of endogenous NaHCO ₃ ), pre-exposure to TCP prior to infection sensitized the NaHCO ₃ -responsive MRSA strain (but not the non-responsive strain) to enhanced clearances by CFX in target tissues. These data support the notion that NaHCO ₃ is acting similarly to WTA synthesis inhibitors, and that such inhibitors have potential translational applications in the treatment of certain MRSA strains in conjunction with specific β-lactam agents.