Influence of Sodium Bicarbonate on Wall Teichoic Acid Synthesis and β-Lactam Sensitization in NaHCO ₃ -Responsive and Nonresponsive Methicillin-Resistant Staphylococcus aureus

Abstract

MRSA is generally viewed as resistant to standard β-lactam antibiotics. However, a NaHCO 3 -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 NaHCO 3 .

Sensitizing methicillin-resistant Staphylococcus aureus (MRSA) to cefuroxime: the synergic effect of bicarbonate and the wall teichoic acid inhibitor ticlopidine

“… b TCP exposure is 32 µg/mL in all conditions. c Data previously published in Ersoy et al ( 12 ). d BSI, bloodstream infection; SSTI, skin and soft tissue infection.…”

“…Previously, both TCP and NaHCO 3 were each shown to sensitize NaHCO 3 -responsive MRSA BSI isolates to the PBP2-specific inhibitor, CFX ( 12 ). In the current cohort, which has been enlarged by the addition of MRSA SSTI isolates, a similar phenotype was observed, wherein NaHCO 3 -responsive MRSA isolates were sensitized to CFX by TCP or NaHCO 3 ; in contrast, the susceptibilities of non-responsive strains were not impacted by these agents ( Table 1 ).…”

“…As mentioned above, we recently demonstrated that NaHCO 3 was capable of altering WTA production in a small cohort of MRSA BSI isolates, and that NaHCO 3 and TCP were similarly capable of sensitizing MRSA to the PBP2-targeting β-lactam, cefuroxime (CFX) ( 12 ). There were no further in vitro synergistic enhancements of NaHCO 3 plus TCP on CFX sensitization by minimum inhibitory concentration (MIC) assay, suggesting that NaHCO 3 and TCP may have the same biological target.…”

“…Mechanistically, NaHCO 3 -mediated susceptibility to CFZ and OXA appears related to multiple impacts on penicillin-binding protein (PBP) 2a expression and functionality ( 9 – 11 ). In addition, NaHCO 3 has been shown to affect the expression and production of components required for PBP2a activity, including the PBP2a chaperone system, vrsA-prsA , and wall teichoic acid (WTA) synthesis ( 9 , 12 ). Of interest, disruption of WTA synthesis, with agents such as ticlopidine (TCP), tarocins, and tunicamycin, is also known to sensitize MRSA to β-lactams, especially those that specifically target PBP2 ( 13 – 16 ).…”

Role of the NaHCO 3 Transporter MpsABC in the NaHCO 3 –β-Lactam-Responsive Phenotype in Methicillin-Resistant Staphylococcus aureus

“…Recent investigations from our laboratory have defined a number of key phenotypic and genotypic characteristics of MRSA strains that distinguish NaHCO 3 -responsive from NaHCO 3 -nonresponsive isolates when exposed to NaHCO 3 , including (i) reduced production of PBP2a (a major determinant of β-lactam resistance); (ii) reduced expression of mecA (a gene responsible for PBP2a production), blaZ (coregulator of PBP2a production), and sarA (required for maintenance of the MRSA phenotype); (iii) reduced expression of pbp4 , vraS , and prsA (required for intramembrane maturation and final folding of PBP2a); (iv) a synergistic impact on killing when NaHCO 3 is combined with host defense cationic peptides; (v) increased β-lactam binding to the MRSA surface and to membrane-localized PBP2a; (vi) the presence of specific genotypes within the ribosome binding site (RBS) and coding regions of mecA (e.g., 246G versus 246E); (vii) an association with the combination of in vitro susceptibility to amoxicillin-clavulanate, specific mecA susceptible genotypes (246G), and specific spa types (t002 or t008); (viii) reductions in wall teichoic acid (WTA) synthesis via posttranslational mechanisms (e.g., gene products involved in peptidoglycan synthesis and functionality); and (ix) enhanced clearance from simulated cardiac vegetations ex vivo , as well as from vegetations and other target tissues in experimental endocarditis in vivo ( 4 , 6 , 7 , 9 – 14 ).…”