Scientific article
Open access

Whole genome sequencing and complete genetic analysis reveals novel pathways to glycopeptide resistance in Staphylococcus aureus

Published inPloS one, vol. 6, no. 6, e21577
Publication date2011

The precise mechanisms leading to the emergence of low-level glycopeptide resistance in Staphylococcus aureus are poorly understood. In this study, we used whole genome deep sequencing to detect differences between two isogenic strains: a parental strain and a stable derivative selected stepwise for survival on 4 µg/ml teicoplanin, but which grows at higher drug concentrations (MIC 8 µg/ml). We uncovered only three single nucleotide changes in the selected strain. Nonsense mutations occurred in stp1, encoding a serine/threonine phosphatase, and in yjbH, encoding a post-transcriptional negative regulator of the redox/thiol stress sensor and global transcriptional regulator, Spx. A missense mutation (G45R) occurred in the histidine kinase sensor of cell wall stress, VraS. Using genetic methods, all single, pairwise combinations, and a fully reconstructed triple mutant were evaluated for their contribution to low-level glycopeptide resistance. We found a synergistic cooperation between dual phospho-signalling systems and a subtle contribution from YjbH, suggesting the activation of oxidative stress defences via Spx. To our knowledge, this is the first genetic demonstration of multiple sensor and stress pathways contributing simultaneously to glycopeptide resistance development. The multifactorial nature of glycopeptide resistance in this strain suggests a complex reprogramming of cell physiology to survive in the face of drug challenge.

  • Anti-Bacterial Agents/pharmacology
  • Drug Resistance, Microbial/genetics
  • Genome, Bacterial/genetics
  • Glycopeptides/pharmacology
  • Microbial Sensitivity Tests
  • Staphylococcus aureus/drug effects/genetics
Citation (ISO format)
RENZONI, Adriana Maria et al. Whole genome sequencing and complete genetic analysis reveals novel pathways to glycopeptide resistance in Staphylococcus aureus. In: PloS one, 2011, vol. 6, n° 6, p. e21577. doi: 10.1371/journal.pone.0021577
Main files (1)
Article (Published version)
ISSN of the journal1932-6203

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