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
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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.
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