Bicarbonate Resensitization of Methicillin-Resistant Staphylococcus aureus to β-Lactam Antibiotics

Area of Science:

• Microbiology
• Infectious Diseases
• Antimicrobial Resistance

Background:

• Endovascular infections caused by methicillin-resistant Staphylococcus aureus (MRSA) pose significant healthcare challenges, particularly infective endocarditis (IE).
• Standard antimicrobial susceptibility testing (AST) often classifies MRSA as resistant to beta-lactams, leading to suboptimal or toxic treatments.
• Developing accurate diagnostic methods for MRSA is crucial for effective patient management.

Purpose of the Study:

• To investigate the impact of sodium bicarbonate (NaHCO3) supplementation on MRSA susceptibility testing.
• To determine if NaHCO3-modified AST can predict the efficacy of beta-lactam antibiotics against MRSA.
• To elucidate the molecular mechanisms underlying altered MRSA susceptibility.

Main Methods:

• Antimicrobial susceptibility testing (AST) of five prototype MRSA strains was performed using standard media with and without NaHCO3 supplementation.
• Experimental MRSA IE models were used to evaluate the clearance of MRSA from tissues following beta-lactam treatment.
• Gene expression analysis of key resistance genes (mecA, sarA) and penicillin-binding protein 2a production was conducted.
• Synergistic killing assays were performed using beta-lactams, LL-37, and NaHCO3-supplemented media.

Main Results:

• Two distinct MRSA phenotypes emerged upon NaHCO3 supplementation: NaHCO3-responsive (susceptible) and NaHCO3-nonresponsive (resistant) to oxacillin and cefazolin.
• These phenotypes accurately predicted MRSA clearance from target tissues in experimental IE models.
• NaHCO3 supplementation reduced mecA and sarA gene expression and penicillin-binding protein 2a production in responsive strains.
• Cefazolin and oxacillin showed synergistic killing of NaHCO3-responsive strains in the presence of LL-37 and NaHCO3.

Conclusions:

• NaHCO3-supplemented AST can differentiate MRSA strains based on their susceptibility to beta-lactams.
• This modified AST approach may identify MRSA infections amenable to beta-lactam therapy.
• The findings provide a potential strategy to optimize treatment for MRSA endovascular infections.