NaHCO3 modulates the bla operon and β-lactam susceptibility in borderline oxacillin-resistant Staphylococcus aureus (BORSA)

Selvi C Ersoy; Sabrina L Madrigal; Richard A Proctor; Henry F Chambers; Yan Q Xiong; Arnold S Bayer

doi:10.1093/jac/dkae455

NaHCO3 modulates the bla operon and β-lactam susceptibility in borderline oxacillin-resistant Staphylococcus aureus (BORSA)

J Antimicrob Chemother. 2024 Dec 20:dkae455. doi: 10.1093/jac/dkae455. Online ahead of print.

Authors

Selvi C Ersoy^{1

2}, Sabrina L Madrigal³, Richard A Proctor⁴, Henry F Chambers⁵, Yan Q Xiong^{1

2}, Arnold S Bayer^{1

2}

Affiliations

¹ Division of Infection Disease, The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
² David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
³ Department of Biological Sciences, CSU Los Angeles, Los Angeles, CA, USA.
⁴ Departments of Medicine and Medical Microbiology/Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
⁵ UCSF School of Medicine, San Francisco, CA, USA.

PMID: 39704154
DOI: 10.1093/jac/dkae455

Abstract

Background: Methicillin-resistant Staphylococcus aureus (MRSA) are resistant to nearly all β-lactam antibiotics under standard testing conditions. However, a novel phenotype exists wherein certain MRSA strains exhibit β-lactam susceptibility in the presence of bicarbonate (termed 'NaHCO3-responsive'), an abundant ion in mammalian tissues and blood. This suggests that specific MRSA infections may be treatable by β-lactams. NaHCO3 responsiveness appears due to effects of NaHCO3 on the expression mecA/PBP2a and other accessory genes required for PBP functionality. mecA expression can be co-regulated by the bla operon regulatory genes, blaI and blaR1.

Objectives: To elucidate the influence of NaHCO3 specifically on the bla operon via investigations of the impact of NaHCO3 on β-lactamase hyper-producing, mecA-negative, borderline oxacillin-resistant Staphylococcus aureus (BORSA) strains.

Methods: Evaluate the effect of NaHCO3 on β-lactam susceptibility via minimum inhibitory concentrations (MIC) assay, expression of genes within the bla operon (blaZ, blaI, blaR1) via RT-qPCR, and β-lactamase (BlaZ) activity via nitrocefinase assay in BORSA.

Results: NaHCO3 enhanced susceptibility to β-lactamase-susceptible β-lactams penicillin and ampicillin. NaHCO3 had no impact on susceptibility to the anti-staphylococcal β-lactams oxacillin and cefazolin, or the anti-MRSA antibiotics vancomycin and daptomycin. NaHCO3 repressed expression of all genes within the bla operon and reduced β-lactamase production.

Conclusions: These data demonstrate that NaHCO3 influences expression of genes within the bla operon, translating to reduced β-lactamase production and enhanced β-lactam susceptibility in BORSA strains. Furthermore, this indicates that the classical blaZ regulators, blaI and blaR1, are the likely mediators of NaHCO3-mediated repression of mecA. However, questions still remain regarding the mechanism via which NaHCO3 regulates the bla operon.

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Grants and funding

1RO1-AI146078/NH/NIH HHS/United States