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Correlation of daptomycin resistance in a clinical Staphylococcus aureus strain with increased cell wall teichoic acid production and D-alanylation

Bertsche, Ute
Weidenmaier, Christopher
Kuehner, Daniel
Yang, Soo-Jin
Baur, Stefanie
Wanner, Stefanie
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Published in Antimicrobial agents and chemotherapy. 2011, vol. 55, no. 8, p. 3922-8
Abstract Cell wall thickening is a common feature among daptomycin-resistant Staphylococcus aureus strains. However, the mechanism(s) leading to this phenotype is unknown. We examined a number of cell wall synthesis pathway parameters in an isogenic strain set of S. aureus bloodstream isolates obtained from a patient with recalcitrant endocarditis who failed daptomycin therapy, including the initial daptomycin-susceptible parental strain (strain 616) and two daptomycin-resistant strains (strains 701 and 703) isolated during daptomycin therapy. Transmission electron microscopy demonstrated significantly thicker cell walls in the daptomycin-resistant strains than in the daptomycin-susceptible strain, a finding which was compatible with significant differences in dry cell weight of strain 616 versus strains 701 to 703 (P < 0.05). Results of detailed analysis of cell wall muropeptide composition, the degree of peptide side chain cross-linkage, and the amount of the peptidoglycan precursor, UDP-MurNAc-pentapeptide, were similar in the daptomycin-susceptible and daptomycin-resistant isolates. In contrast, the daptomycin-resistant strains contained less O-acetylated peptidoglycan. Importantly, both daptomycin-resistant strains synthesized significantly more wall teichoic acid (WTA) than the parental strain (P < 0.001). Moreover, the proportion of D-alanylated WTA species was substantially higher in the daptomycin-resistant strains than in the daptomycin-susceptible parental strain (P < 0.05 in comparing strain 616 versus strain 701). The latter phenotypic findings correlated with (i) enhanced tagA and dltA gene expression, respectively, and (ii) an increase in surface positive charge observed in the daptomycin-resistant versus daptomycin-susceptible isolates. Collectively, these data suggest that increases in WTA synthesis and the degree of its D-alanylation may play a major role in the daptomycin-resistant phenotype in some S. aureus strains.
Keywords Alanine/metabolismAnti-Bacterial Agents/analysis/pharmacology/therapeutic useBacterial Proteins/biosynthesisCell Wall/chemistry/metabolismDaptomycin/analysis/pharmacology/therapeutic useDrug Resistance, BacterialEndocarditis, Bacterial/microbiologyHumansLipoproteins/biosynthesisMicrobial Sensitivity TestsMicroscopy, Electron, TransmissionPeptidoglycan/biosynthesisStaphylococcal Infections/drug therapy/microbiologyStaphylococcus aureus/drug effects/isolation & purification/metabolismTeichoic Acids/biosynthesisUridine Diphosphate N-Acetylmuramic Acid/analogs & derivatives/biosynthesis
PMID: 21606222
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Research group Analyse génomique et fonctionnelle du staphylocoque doré (604)
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BERTSCHE, Ute et al. Correlation of daptomycin resistance in a clinical Staphylococcus aureus strain with increased cell wall teichoic acid production and D-alanylation. In: Antimicrobial agents and chemotherapy, 2011, vol. 55, n° 8, p. 3922-8. doi: 10.1128/AAC.01226-10 https://archive-ouverte.unige.ch/unige:25445

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Deposited on : 2013-01-14

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