Influence of Sodium Bicarbonate on Wall Teichoic Acid Synthesis and β-Lactam Sensitization in NaHCO3-Responsive and Nonresponsive Methicillin-Resistant Staphylococcus aureus
ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) strains pose major treatment challenges due to their innate resistance to most β-lactams under standard in vitro antimicrobial susceptibility testing conditions. A novel phenotype among MRSA, termed “NaHCO3 responsiveness,” where certain st...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2022-12-01
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| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.03422-22 |
| _version_ | 1797979677024845824 |
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| author | Selvi C. Ersoy Barbara Gonçalves Gonçalo Cavaco Adhar C. Manna Rita G. Sobral Cynthia C. Nast Richard A. Proctor Henry F. Chambers Ambrose Cheung Arnold S. Bayer |
| author_facet | Selvi C. Ersoy Barbara Gonçalves Gonçalo Cavaco Adhar C. Manna Rita G. Sobral Cynthia C. Nast Richard A. Proctor Henry F. Chambers Ambrose Cheung Arnold S. Bayer |
| author_sort | Selvi C. Ersoy |
| collection | DOAJ |
| description | ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) strains pose major treatment challenges due to their innate resistance to most β-lactams under standard in vitro antimicrobial susceptibility testing conditions. A novel phenotype among MRSA, termed “NaHCO3 responsiveness,” where certain strains display increased susceptibility to β-lactams in the presence of NaHCO3, has been identified among a relatively large proportion of MRSA isolates. One underlying mechanism of NaHCO3 responsiveness appears to be related to decreased expression and altered functionality of several genes and proteins involved in cell wall synthesis and maturation. Here, we studied the impact of NaHCO3 on wall teichoic acid (WTA) synthesis, a process intimately linked to peptidoglycan (PG) synthesis and functionality, in NaHCO3-responsive versus -nonresponsive MRSA isolates. NaHCO3 sensitized responsive MRSA strains to cefuroxime, a specific penicillin-binding protein 2 (PBP2)-inhibitory β-lactam known to synergize with early WTA synthesis inhibitors (e.g., ticlopidine). Combining cefuroxime with ticlopidine with or without NaHCO3 suggested that these latter two agents target the same step in WTA synthesis. Further, NaHCO3 decreased the abundance and molecular weight of WTA only in responsive strains. Additionally, NaHCO3 stimulated increased autolysis and aberrant cell division in responsive strains, two phenotypes associated with disruption of WTA synthesis. Of note, studies of key genes involved in the WTA biosynthetic pathway (e.g., tarO, tarG, dltA, and fmtA) indicated that the inhibitory impact of NaHCO3 on WTA biosynthesis in responsive strains likely occurred posttranslationally. IMPORTANCE MRSA is generally viewed as resistant to standard β-lactam antibiotics. However, a NaHCO3-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 NaHCO3. This phenotype correlates with increased MRSA clearance in vivo by standard β-lactam antibiotics, suggesting that patients with infections caused by such MRSA strains might be amenable to treatment with β-lactams. The mechanism(s) behind this phenotype is not fully understood but appears to involve mecA-PBP2a production and maturation axes. Our study adds significantly to this body of knowledge in terms of additional mechanistic targets of NaHCO3 in selected MRSA strains. This investigation demonstrates that NaHCO3 has direct impacts on S. aureus wall teichoic acid biosynthesis in NaHCO3-responsive MRSA. These findings provide an additional target for new agents being designed to synergistically kill MRSA using β-lactam antibiotics. |
| first_indexed | 2024-04-11T05:42:39Z |
| format | Article |
| id | doaj.art-8917d943fcd94570abddfd92810f8294 |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-04-11T05:42:39Z |
| publishDate | 2022-12-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-8917d943fcd94570abddfd92810f82942022-12-22T04:42:26ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972022-12-0110610.1128/spectrum.03422-22Influence of Sodium Bicarbonate on Wall Teichoic Acid Synthesis and β-Lactam Sensitization in NaHCO3-Responsive and Nonresponsive Methicillin-Resistant Staphylococcus aureusSelvi C. Ersoy0Barbara Gonçalves1Gonçalo Cavaco2Adhar C. Manna3Rita G. Sobral4Cynthia C. Nast5Richard A. Proctor6Henry F. Chambers7Ambrose Cheung8Arnold S. Bayer9The Lundquist Institute, Torrance, California, USALaboratory of Molecular Microbiology of Bacterial Pathogens, UCIBIO, Applied Molecular Biosciences Unit, Department of Life Sciences, Nova School of Science and Technology, Universidade Nova de Lisboa, Caparica, PortugalLaboratory of Molecular Microbiology of Bacterial Pathogens, UCIBIO, Applied Molecular Biosciences Unit, Department of Life Sciences, Nova School of Science and Technology, Universidade Nova de Lisboa, Caparica, PortugalDepartment of Microbiology & Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USALaboratory of Molecular Microbiology of Bacterial Pathogens, UCIBIO, Applied Molecular Biosciences Unit, Department of Life Sciences, Nova School of Science and Technology, Universidade Nova de Lisboa, Caparica, PortugalCedars-Sinai Medical Center, Los Angeles, California, USADepartment of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USAUCSF School of Medicine, San Francisco, California, USADepartment of Microbiology & Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USAThe Lundquist Institute, Torrance, California, USAABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) strains pose major treatment challenges due to their innate resistance to most β-lactams under standard in vitro antimicrobial susceptibility testing conditions. A novel phenotype among MRSA, termed “NaHCO3 responsiveness,” where certain strains display increased susceptibility to β-lactams in the presence of NaHCO3, has been identified among a relatively large proportion of MRSA isolates. One underlying mechanism of NaHCO3 responsiveness appears to be related to decreased expression and altered functionality of several genes and proteins involved in cell wall synthesis and maturation. Here, we studied the impact of NaHCO3 on wall teichoic acid (WTA) synthesis, a process intimately linked to peptidoglycan (PG) synthesis and functionality, in NaHCO3-responsive versus -nonresponsive MRSA isolates. NaHCO3 sensitized responsive MRSA strains to cefuroxime, a specific penicillin-binding protein 2 (PBP2)-inhibitory β-lactam known to synergize with early WTA synthesis inhibitors (e.g., ticlopidine). Combining cefuroxime with ticlopidine with or without NaHCO3 suggested that these latter two agents target the same step in WTA synthesis. Further, NaHCO3 decreased the abundance and molecular weight of WTA only in responsive strains. Additionally, NaHCO3 stimulated increased autolysis and aberrant cell division in responsive strains, two phenotypes associated with disruption of WTA synthesis. Of note, studies of key genes involved in the WTA biosynthetic pathway (e.g., tarO, tarG, dltA, and fmtA) indicated that the inhibitory impact of NaHCO3 on WTA biosynthesis in responsive strains likely occurred posttranslationally. IMPORTANCE MRSA is generally viewed as resistant to standard β-lactam antibiotics. However, a NaHCO3-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 NaHCO3. This phenotype correlates with increased MRSA clearance in vivo by standard β-lactam antibiotics, suggesting that patients with infections caused by such MRSA strains might be amenable to treatment with β-lactams. The mechanism(s) behind this phenotype is not fully understood but appears to involve mecA-PBP2a production and maturation axes. Our study adds significantly to this body of knowledge in terms of additional mechanistic targets of NaHCO3 in selected MRSA strains. This investigation demonstrates that NaHCO3 has direct impacts on S. aureus wall teichoic acid biosynthesis in NaHCO3-responsive MRSA. These findings provide an additional target for new agents being designed to synergistically kill MRSA using β-lactam antibiotics.https://journals.asm.org/doi/10.1128/spectrum.03422-22methicillin-resistant Staphylococcus aureus (MRSA)sodium bicarbonatepenicillin-binding proteins (PBPs)peptidoglycan (PG)wall teichoic acid (WTA)β-lactams |
| spellingShingle | Selvi C. Ersoy Barbara Gonçalves Gonçalo Cavaco Adhar C. Manna Rita G. Sobral Cynthia C. Nast Richard A. Proctor Henry F. Chambers Ambrose Cheung Arnold S. Bayer Influence of Sodium Bicarbonate on Wall Teichoic Acid Synthesis and β-Lactam Sensitization in NaHCO3-Responsive and Nonresponsive Methicillin-Resistant Staphylococcus aureus Microbiology Spectrum methicillin-resistant Staphylococcus aureus (MRSA) sodium bicarbonate penicillin-binding proteins (PBPs) peptidoglycan (PG) wall teichoic acid (WTA) β-lactams |
| title | Influence of Sodium Bicarbonate on Wall Teichoic Acid Synthesis and β-Lactam Sensitization in NaHCO3-Responsive and Nonresponsive Methicillin-Resistant Staphylococcus aureus |
| title_full | Influence of Sodium Bicarbonate on Wall Teichoic Acid Synthesis and β-Lactam Sensitization in NaHCO3-Responsive and Nonresponsive Methicillin-Resistant Staphylococcus aureus |
| title_fullStr | Influence of Sodium Bicarbonate on Wall Teichoic Acid Synthesis and β-Lactam Sensitization in NaHCO3-Responsive and Nonresponsive Methicillin-Resistant Staphylococcus aureus |
| title_full_unstemmed | Influence of Sodium Bicarbonate on Wall Teichoic Acid Synthesis and β-Lactam Sensitization in NaHCO3-Responsive and Nonresponsive Methicillin-Resistant Staphylococcus aureus |
| title_short | Influence of Sodium Bicarbonate on Wall Teichoic Acid Synthesis and β-Lactam Sensitization in NaHCO3-Responsive and Nonresponsive Methicillin-Resistant Staphylococcus aureus |
| title_sort | influence of sodium bicarbonate on wall teichoic acid synthesis and β lactam sensitization in nahco3 responsive and nonresponsive methicillin resistant staphylococcus aureus |
| topic | methicillin-resistant Staphylococcus aureus (MRSA) sodium bicarbonate penicillin-binding proteins (PBPs) peptidoglycan (PG) wall teichoic acid (WTA) β-lactams |
| url | https://journals.asm.org/doi/10.1128/spectrum.03422-22 |
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