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

2022-11-15Artigo científico Acesso aberto
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dc.contributor.authorErsoy, Selvi C.
dc.contributor.authorGonçalves, Bárbara
dc.contributor.authorCavaco, Gonçalo
dc.contributor.authorManna, Adhar C.
dc.contributor.authorSobral, Rita G
dc.contributor.authorNast, Cynthia C.
dc.contributor.authorProctor, Richard A.
dc.contributor.authorChambers, Henry F.
dc.contributor.authorCheung, Ambrose
dc.contributor.authorBayer, Arnold S
dc.contributor.institutionDCV - Departamento de Ciências da Vida
dc.contributor.institutionUCIBIO - Applied Molecular Biosciences Unit
dc.contributor.pblAmerican Society for Microbiology
dc.date.accessioned2022-12-09T22:15:26Z
dc.date.available2022-12-09T22:15:26Z
dc.date.issued2022-11-15
dc.descriptiongrant from the National Institutes of Health:1RO1-AI146078 (to A.S.B.). LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy-i4HB.
dc.description.abstractMethicillin-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 "NaHCO 3 responsiveness," where certain strains display increased susceptibility to β-lactams in the presence of NaHCO 3, has been identified among a relatively large proportion of MRSA isolates. One underlying mechanism of NaHCO 3 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 NaHCO 3 on wall teichoic acid (WTA) synthesis, a process intimately linked to peptidoglycan (PG) synthesis and functionality, in NaHCO 3-responsive versus -nonresponsive MRSA isolates. NaHCO 3 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 NaHCO 3 suggested that these latter two agents target the same step in WTA synthesis. Further, NaHCO 3 decreased the abundance and molecular weight of WTA only in responsive strains. Additionally, NaHCO 3 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 NaHCO 3 on WTA biosynthesis in responsive strains likely occurred posttranslationally. IMPORTANCE 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. 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 NaHCO 3 in selected MRSA strains. This investigation demonstrates that NaHCO 3 has direct impacts on S. aureus wall teichoic acid biosynthesis in NaHCO 3-responsive MRSA. These findings provide an additional target for new agents being designed to synergistically kill MRSA using β-lactam antibiotics.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent14
dc.format.extent1616214
dc.identifier.doi10.1128/spectrum.03422-22
dc.identifier.issn2165-0497
dc.identifier.otherPURE: 47879302
dc.identifier.otherPURE UUID: 1e6582a0-d01c-4be9-9f80-99ce9f0e6db2
dc.identifier.otherPubMed: 36377886
dc.identifier.otherWOS: 000885381100001
dc.identifier.otherScopus: 85144636170
dc.identifier.otherORCID: /0000-0003-4533-7531/work/201987301
dc.identifier.urihttp://hdl.handle.net/10362/146097
dc.language.isoeng
dc.peerreviewedyes
dc.relationinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F04378%2F2020/PT
dc.relationApplied Molecular Biosciences Unit
dc.relationApplied Molecular Biosciences Unit
dc.relationFighting Staphylococcus aureus - Peptidoglycan amidation as a new target
dc.subjectmethicillin-resistant Staphylococcus aureus (MRSA),
dc.subjectsodium bicarbonate
dc.subjectpenicillin-binding proteins (PBPs)
dc.subjectpeptidoglycan (PG)
dc.subjectwall teichoic acid (WTA)
dc.subjectlactams
dc.subjectmethicillin resistance
dc.titleInfluence of Sodium Bicarbonate on Wall Teichoic Acid Synthesis and β-Lactam Sensitization in NaHCO 3-Responsive and Nonresponsive Methicillin-Resistant Staphylococcus aureus.en
dc.typejournal article
degois.publication.issue6
degois.publication.titleMicrobiology Spectrum
degois.publication.volume10
dspace.entity.typePublication
oaire.awardNumberUIDP/04378/2020
oaire.awardNumberUIDB/04378/2020
oaire.awardNumberPTDC/BIA-MIC/31645/2017
oaire.awardTitleApplied Molecular Biosciences Unit
oaire.awardTitleApplied Molecular Biosciences Unit
oaire.awardTitleFighting Staphylococcus aureus - Peptidoglycan amidation as a new target
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F04378%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04378%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FBIA-MIC%2F31645%2F2017/PT
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream3599-PPCDT
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccess
relation.isProjectOfPublication38373452-5c9c-4724-8def-f03314ecce0e
relation.isProjectOfPublicatione07cf232-4705-4b5b-b2c4-af8f25311076
relation.isProjectOfPublicationa163b734-21a2-4ba4-9d27-c40f344ff3e6
relation.isProjectOfPublication.latestForDiscoverye07cf232-4705-4b5b-b2c4-af8f25311076

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