Selvi C. Ersoy , Sabrina L. Madrigal , Liang Chen , Jose Mediavilla , Barry Kreiswirth , Evelyn A. Flores , Loren G. Miller , Yan Q. Xiong , Ewan M. Harrison , Beth Blane , Sharon J. Peacock , Robin Patel , Henry F. Chambers , Arnold S. Bayer , Richard A. Proctor
{"title":"皮肤和软组织感染（SSTIs）耐甲氧西林金黄色葡萄球菌（MRSA）分离株nahco3应答表型的表型和基因型相关性","authors":"Selvi C. Ersoy , Sabrina L. Madrigal , Liang Chen , Jose Mediavilla , Barry Kreiswirth , Evelyn A. Flores , Loren G. Miller , Yan Q. Xiong , Ewan M. Harrison , Beth Blane , Sharon J. Peacock , Robin Patel , Henry F. Chambers , Arnold S. Bayer , Richard A. Proctor","doi":"10.1016/j.cmi.2024.11.034","DOIUrl":null,"url":null,"abstract":"<div><h3>Objectives</h3><div>The objective of this study is to assess the frequency of the novel sodium bicarbonate (NaHCO<sub>3</sub>)-responsive phenotype, wherein clinical methicillin-resistant <em>Staphylococcus aureus</em> (MRSA) isolates are rendered susceptible to standard-of-care β-lactams in the presence of NaHCO<sub>3</sub>, in a collection of 103 clinical U.S. MRSA skin and soft-tissue infection (SSTI) isolates and 22 clinical European SSTI isolates. This study determined the correlation between specific phenotypic and genotypic metrics and the NaHCO<sub>3</sub>-responsive phenotype among U.S. SSTI isolates.</div></div><div><h3>Methods</h3><div>Antimicrobial susceptibility testing was performed to determine susceptibility phenotypes. Targeted and whole-genome sequencing with a genome-wide sequence analysis were conducted to identify specific and novel genotypes of interest that may be associated with the NaHCO<sub>3</sub>-responsive phenotype. Gene expression analysis and targeted gene deletion were performed to assess the role of a specific novel genetic locus in the NaHCO<sub>3</sub>-responsive phenotype.</div></div><div><h3>Results</h3><div>The NaHCO<sub>3</sub>-responsive phenotype was identified in 78/103 U.S. isolates and 4/22 UK isolates to cefazolin (CFZ), and in 17/103 U.S. isolates and 1/22 UK isolates to oxacillin. In U.S. isolates, a significant association was identified between NaHCO<sub>3</sub>-responsiveness to CFZ and: (a) susceptibility to amoxicillin–clavulanate; (b) a specific <em>mecA</em> genotype; (c) clonal complex type 8; and (d) <em>spa</em> type t008. Genome-wide sequence analysis identified single nucleotide polymorphisms (SNPs) in an AraC family regulator (SAUSA300_RS00540) to be exclusively found in NaHCO<sub>3</sub>-non-responsive SSTI strains. <em>In vitro</em> HCO<sub>3</sub> exposures of NaHCO<sub>3</sub>-responsive strains, but not -non-responsive strains, caused >2-fold upregulated expression of this gene. Deletion of this gene rendered NaHCO<sub>3</sub>-responsive strain MRSA 11/11 no longer NaHCO<sub>3</sub>-responsive to CFZ; we have termed this gene the staphylococcal AraC bicarbonate-response regulator.</div></div><div><h3>Discussion</h3><div>NaHCO<sub>3</sub>-responsiveness is highly associated with clonal complex type 8/<em>spa</em> type t008, a commonly circulating genetic background in North America. The AraC bicarbonate-response regulator, staphylococcal AraC bicarbonate-response regulator, appears to be associated with the mechanism of NaHCO<sub>3</sub>-responsiveness, but more work is needed to verify.</div></div>","PeriodicalId":10444,"journal":{"name":"Clinical Microbiology and Infection","volume":"31 4","pages":"Pages 588-593"},"PeriodicalIF":8.7000,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Phenotypic and genotypic correlates of the sodium bicarbonate-responsive phenotype among methicillin-resistant Staphylococcus aureus isolates from skin and soft-tissue infections\",\"authors\":\"Selvi C. Ersoy , Sabrina L. Madrigal , Liang Chen , Jose Mediavilla , Barry Kreiswirth , Evelyn A. Flores , Loren G. Miller , Yan Q. Xiong , Ewan M. Harrison , Beth Blane , Sharon J. Peacock , Robin Patel , Henry F. Chambers , Arnold S. Bayer , Richard A. Proctor\",\"doi\":\"10.1016/j.cmi.2024.11.034\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Objectives</h3><div>The objective of this study is to assess the frequency of the novel sodium bicarbonate (NaHCO<sub>3</sub>)-responsive phenotype, wherein clinical methicillin-resistant <em>Staphylococcus aureus</em> (MRSA) isolates are rendered susceptible to standard-of-care β-lactams in the presence of NaHCO<sub>3</sub>, in a collection of 103 clinical U.S. MRSA skin and soft-tissue infection (SSTI) isolates and 22 clinical European SSTI isolates. This study determined the correlation between specific phenotypic and genotypic metrics and the NaHCO<sub>3</sub>-responsive phenotype among U.S. SSTI isolates.</div></div><div><h3>Methods</h3><div>Antimicrobial susceptibility testing was performed to determine susceptibility phenotypes. Targeted and whole-genome sequencing with a genome-wide sequence analysis were conducted to identify specific and novel genotypes of interest that may be associated with the NaHCO<sub>3</sub>-responsive phenotype. Gene expression analysis and targeted gene deletion were performed to assess the role of a specific novel genetic locus in the NaHCO<sub>3</sub>-responsive phenotype.</div></div><div><h3>Results</h3><div>The NaHCO<sub>3</sub>-responsive phenotype was identified in 78/103 U.S. isolates and 4/22 UK isolates to cefazolin (CFZ), and in 17/103 U.S. isolates and 1/22 UK isolates to oxacillin. In U.S. isolates, a significant association was identified between NaHCO<sub>3</sub>-responsiveness to CFZ and: (a) susceptibility to amoxicillin–clavulanate; (b) a specific <em>mecA</em> genotype; (c) clonal complex type 8; and (d) <em>spa</em> type t008. Genome-wide sequence analysis identified single nucleotide polymorphisms (SNPs) in an AraC family regulator (SAUSA300_RS00540) to be exclusively found in NaHCO<sub>3</sub>-non-responsive SSTI strains. <em>In vitro</em> HCO<sub>3</sub> exposures of NaHCO<sub>3</sub>-responsive strains, but not -non-responsive strains, caused >2-fold upregulated expression of this gene. Deletion of this gene rendered NaHCO<sub>3</sub>-responsive strain MRSA 11/11 no longer NaHCO<sub>3</sub>-responsive to CFZ; we have termed this gene the staphylococcal AraC bicarbonate-response regulator.</div></div><div><h3>Discussion</h3><div>NaHCO<sub>3</sub>-responsiveness is highly associated with clonal complex type 8/<em>spa</em> type t008, a commonly circulating genetic background in North America. The AraC bicarbonate-response regulator, staphylococcal AraC bicarbonate-response regulator, appears to be associated with the mechanism of NaHCO<sub>3</sub>-responsiveness, but more work is needed to verify.</div></div>\",\"PeriodicalId\":10444,\"journal\":{\"name\":\"Clinical Microbiology and Infection\",\"volume\":\"31 4\",\"pages\":\"Pages 588-593\"},\"PeriodicalIF\":8.7000,\"publicationDate\":\"2025-04-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical Microbiology and Infection\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1198743X24005652\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/12/1 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"INFECTIOUS DISEASES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Microbiology and Infection","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1198743X24005652","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/12/1 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"INFECTIOUS DISEASES","Score":null,"Total":0}
Phenotypic and genotypic correlates of the sodium bicarbonate-responsive phenotype among methicillin-resistant Staphylococcus aureus isolates from skin and soft-tissue infections
Objectives
The objective of this study is to assess the frequency of the novel sodium bicarbonate (NaHCO3)-responsive phenotype, wherein clinical methicillin-resistant Staphylococcus aureus (MRSA) isolates are rendered susceptible to standard-of-care β-lactams in the presence of NaHCO3, in a collection of 103 clinical U.S. MRSA skin and soft-tissue infection (SSTI) isolates and 22 clinical European SSTI isolates. This study determined the correlation between specific phenotypic and genotypic metrics and the NaHCO3-responsive phenotype among U.S. SSTI isolates.
Methods
Antimicrobial susceptibility testing was performed to determine susceptibility phenotypes. Targeted and whole-genome sequencing with a genome-wide sequence analysis were conducted to identify specific and novel genotypes of interest that may be associated with the NaHCO3-responsive phenotype. Gene expression analysis and targeted gene deletion were performed to assess the role of a specific novel genetic locus in the NaHCO3-responsive phenotype.
Results
The NaHCO3-responsive phenotype was identified in 78/103 U.S. isolates and 4/22 UK isolates to cefazolin (CFZ), and in 17/103 U.S. isolates and 1/22 UK isolates to oxacillin. In U.S. isolates, a significant association was identified between NaHCO3-responsiveness to CFZ and: (a) susceptibility to amoxicillin–clavulanate; (b) a specific mecA genotype; (c) clonal complex type 8; and (d) spa type t008. Genome-wide sequence analysis identified single nucleotide polymorphisms (SNPs) in an AraC family regulator (SAUSA300_RS00540) to be exclusively found in NaHCO3-non-responsive SSTI strains. In vitro HCO3 exposures of NaHCO3-responsive strains, but not -non-responsive strains, caused >2-fold upregulated expression of this gene. Deletion of this gene rendered NaHCO3-responsive strain MRSA 11/11 no longer NaHCO3-responsive to CFZ; we have termed this gene the staphylococcal AraC bicarbonate-response regulator.
Discussion
NaHCO3-responsiveness is highly associated with clonal complex type 8/spa type t008, a commonly circulating genetic background in North America. The AraC bicarbonate-response regulator, staphylococcal AraC bicarbonate-response regulator, appears to be associated with the mechanism of NaHCO3-responsiveness, but more work is needed to verify.
期刊介绍：
Clinical Microbiology and Infection (CMI) is a monthly journal published by the European Society of Clinical Microbiology and Infectious Diseases. It focuses on peer-reviewed papers covering basic and applied research in microbiology, infectious diseases, virology, parasitology, immunology, and epidemiology as they relate to therapy and diagnostics.
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