Abstract
Comparative genomic sequencing of laboratory-derived vancomycin-intermediate Staphylococcus aureus (VISA) (MM66-3 and MM66-4) revealed unique mutations in both MM66-3 (in apt and ssaA6), and MM66-4 (in apt and walK), compared to hetero-VISA parent strain MM66. Transcriptional profiling revealed that both MM66 VISA shared 79 upregulated genes and eight downregulated genes. Of these, 30.4% of the upregulated genes were associated with the cell envelope, whereas 75% of the downregulated genes were associated with virulence. In concordance with mutations and transcriptome alterations, both VISA strains demonstrated reduced autolysis, reduced growth in the presence of salt and reduced virulence factor activity. In addition to mutations in genes linked to cell wall metabolism (ssaA6 and walK), the same mutation in apt which encodes adenine phosphoribosyltransferase, was confirmed in both MM66 VISA. Apt plays a role in both adenine metabolism and accumulation and both MM66 VISA grew better than MM66 in the presence of adenine or 2-fluoroadenine indicating a reduction in the accumulation of these growth inhibiting compounds in the VISA strains. MM66 apt mutants isolated via 2-fluoroadenine selection also demonstrated reduced susceptibility to the cell wall lytic dye Congo red and vancomycin. Finding that apt mutations contribute to reduced vancomycin susceptibility once again suggests a role for altered purine metabolism in a VISA mechanism.
Highlights
Staphylococcus aureus is a notorious human pathogen that is associated with both hospital- and community-acquired infections
With the exception of the apt mutation, this proposal is in line with a number of previous studies that demonstrate the importance of loss of function mutations in vancomycin-intermediate S. aureus (VISA) mechanisms that directly affect cell wall physiology [3,27,28,55]
While ssaA6 is a new mutation reported for VISA, it is not difficult to envision a role for a mutated autolysin gene in the MM66-3 mechanism since autolytic activity and autolysin gene expression are commonly reduced in VISA strains [3,27,28,55,56]
Summary
Staphylococcus aureus is a notorious human pathogen that is associated with both hospital- and community-acquired infections. Since the emergence of multidrug-resistant methicillin-resistant S. aureus (MRSA), treatment of infections caused by these organisms has become challenging [1]. The glycopeptide antibiotic vancomycin remains a clinically proven drug for the treatment of serious MRSA infections [2]. The increased use of vancomycin, in large part due to the increased incidence of MRSA infections, eventually led to the selection of S. aureus strains that demonstrated reduced susceptibility and resistance to vancomycin. Based on vancomycin MICs, S. aureus isolates are classified as vancomycin-susceptible S. aureus (vancomycin MIC ≤ 2 mg/L), vancomycin-intermediate S. aureus (VISA) (MIC ≥ 4 mg/L), and vancomycin-resistant S. aureus (VRSA) (MIC ≥ 16 mg/L) [2]. A type of VISA termed hetero-VISA (hVISA) initially demonstrate vancomycin MICs of ≤ 2 mg/L, yet upon exposure to vancomycin produce stable VISA subpopulations [2,3]
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