Phenotypic and genotypic correlates of the sodium bicarbonate-responsive phenotype among methicillin-resistant Staphylococcus aureus isolates from skin and soft-tissue infections.
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":"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":"<p><strong>Objectives: </strong>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 Staphylococcus aureus (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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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 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 NaHCO<sub>3</sub>-non-responsive SSTI strains. In vitro 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.</p><p><strong>Discussion: </strong>NaHCO<sub>3</sub>-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 NaHCO<sub>3</sub>-responsiveness, but more work is needed to verify.</p>","PeriodicalId":10444,"journal":{"name":"Clinical Microbiology and Infection","volume":" ","pages":""},"PeriodicalIF":10.9000,"publicationDate":"2024-12-01","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://doi.org/10.1016/j.cmi.2024.11.034","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"INFECTIOUS DISEASES","Score":null,"Total":0}
引用次数: 0
Abstract
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.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
