Sensitizing Methicillin-resistant (MRSA) to Cefuroxime: the Synergic Effect of Bicarbonate and the Wall Teichoic Acid Inhibitor Ticlopidine

Methicillin-resistant (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 . A phenotype termed "NaHCO-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, and ; moreover, such "NaHCO-responsive" isolates can be effectively cleared by β-lactams from target tissues in experimental infective endocarditis (IE). One mechanistic impact of NaHCO exposure on NaHCO-responsive MRSA is to repress WTA synthesis. This NaHCO effect mimics the phenotype of -deficient MRSA, including sensitization to the PBP2-targeting β-lactam, cefuroxime (CFX). Herein, we further investigated the impacts of NaHCO 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 and/or TCP enhanced susceptibility to CFX , by both minimum inhibitor concentration (MIC) and time-kill assays, as well as in an simulated endocarditis vegetations (SEV) model, in NaHCO-responsive MRSA. Furthermore, in experimental IE (presumably in the presence of endogenous NaHCO), pre-exposure to TCP prior to infection sensitized the NaHCO-responsive MRSA strain (but not the non-responsive strain) to enhanced clearances by CFX in target tissues. These data support the notion that NaHCO 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.