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Preliminary analysis of the genetic basis for vancomycin resistance in Staphylococcus aureus strain Mu50
Matthew B Avison1, Peter M Bennett, Robin A Howe
1Bristol Centre for Antimicrobial Research and Evaluation, Department of Biochemistry, University of Bristol, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK. Matthewb.Avison@bris.ac.uk
Abstract:
Glycopeptides, such as vancomycin, are frequently the antibiotics of choice for treatment of infections caused by the now common methicillin-resistant Staphylococcus aureus (MRSA). Incidences of vancomycin resistance in S. aureus (VRSA) have been increasing worldwide for the last 5 years. Complex mechanisms producing changes in cell wall content and composition generate the VRSA phenotype, but the genetic basis of these changes has not yet been determined. To facilitate the genetic investigation, entire genome sequences of the archetypal VRSA (Mu50), and vancomycin-susceptible MRSA strains N315, EMRSA 16 and COL were compared. The in silico analysis revealed several loss-of-function mutations in Mu50, affecting important cell wall biosynthesis and intermediary metabolism genes, not previously reported. The new findings provide further evidence for the hypothesis that vancomycin resistance in Mu50 is due to fundamental changes, important to metabolic pathways that impinge on peptidoglycan biosynthesis. These observations will inform targeted experiments aimed at a complete understanding of the mechanism(s) of vancomycin resistance in S. aureus Mu50 and other VRSA strains.
Insights
Vancomycin resistance in Staphylococcus aureus (VRSA) is increasing. Whole genome sequencing revealed loss-of-function mutations in cell wall biosynthesis and metabolism genes in the VRSA strain Mu50, suggesting a complex genetic basis.
Area of Science:
- Microbiology
- Genomics
- Antibiotic Resistance
Background:
- Methicillin-resistant Staphylococcus aureus (MRSA) infections are common, often treated with vancomycin.
- Increasing incidences of vancomycin-resistant S. aureus (VRSA) worldwide pose a significant clinical challenge.
- The genetic underpinnings of VRSA phenotype, involving cell wall alterations, remain largely undetermined.
Purpose of the Study:
- To investigate the genetic basis of vancomycin resistance in Staphylococcus aureus.
- To compare the whole genome sequences of VRSA strain Mu50 with susceptible MRSA strains.
Main Methods:
- Whole genome sequencing of VRSA (Mu50) and vancomycin-susceptible MRSA strains (N315, EMRSA 16, COL).
- In silico comparative genomic analysis to identify genetic differences.
Main Results:
- Identification of several novel loss-of-function mutations in the Mu50 genome.
- Mutations were found in genes critical for cell wall biosynthesis and intermediary metabolism.
- These genetic alterations were not previously reported in VRSA.
Conclusions:
- Vancomycin resistance in S. aureus Mu50 is likely due to fundamental metabolic pathway changes impacting peptidoglycan biosynthesis.
- The identified mutations provide a foundation for targeted experiments to elucidate VRSA mechanisms.
- Findings will inform future research on vancomycin resistance in S. aureus.