Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases · 2024
Phenotypic and genotypic correlates of the sodium bicarbonate-responsive phenotype among methicillin-resistant Staphylococcus aureus isolates from skin and soft-tissue infections.
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Ersoy Selvi C, Madrigal Sabrina L, Chen Liang, Mediavilla Jose, Kreiswirth Barry, Flores Evelyn A, Miller Loren G, Xiong Yan Q, Harrison Ewan M, Blane Beth, Peacock Sharon J, Patel Robin, Chambers Henry F, Bayer Arnold S, Proctor Richard A
Аннотация
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.
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.