Serial daptomycin selection generates daptomycin-nonsusceptible Staphylococcus aureus strains with a heterogeneous vancomycin-intermediate phenotype

Ilana Lopes Baratella Da Cunha Camargo, Hui Min Neoh, Longzhu Cui, Keiichi Hiramatsu

Research output: Contribution to journalArticle

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Abstract

In order to better understand the mechanism of daptomycin resistance, we generated a daptomycinnonsusceptible derivative strain, strain 10*3d1 (MIC = 3.0 μg/ml), by in vitro exposure of methicillin-resistant Staphylococcus aureus strain N315ΔIP (MIC = 0.5 μg/ml) to daptomycin. We also obtained a daptomycin-susceptible phenotypic revertant strain, strain 10*3d1-10 (MIC = 1.0 μg/ml), by passaging 10*3d1 in drug-free medium for 10 days. The resultant triple-isogenic strains were analyzed for their phenotypes and gene expression by microarray analysis. No significant differences in the membrane fluidities of 10*3d1 and 10*3d1-10 compared to the membrane fluidity of N315ΔIP were observed. Resistant strain 10*3d1 had the highest membrane potential, followed by strains 10*3d1-10 and N315ΔIP. The vancomycin and teicoplanin MICs also increased. Teichoic acid genes (tagA, tagG), mprF encoding lysyl-phosphatidylglycerol, and cls encoding cardiolipin synthase were downregulated in 10*3d1 and 10*3d1-10. The vraF and vraG genes, which encode ATP binding cassette transporter proteins, were upregulated in 10*3d1. The vraSR two-component regulatory system was upregulated, and electron microscopy revealed that the cell wall of 10*3d1 was significantly thicker than that of the parental strain. Taken together, daptomycin exposure selected a daptomycin-nonsusceptible strain with a phenotype similar to that of heterogeneous vancomycin-intermediate S. aureus and a transcription profile that partially overlapped that of heterogeneous vancomycin-intermediate S. aureus.

Original languageEnglish
Pages (from-to)4289-4299
Number of pages11
JournalAntimicrobial Agents and Chemotherapy
Volume52
Issue number12
DOIs
Publication statusPublished - Dec 2008

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Daptomycin
Vancomycin
Staphylococcus aureus
Phenotype
Membrane Fluidity
Teichoic Acids
Teicoplanin
ATP-Binding Cassette Transporters
Microarray Analysis
Methicillin-Resistant Staphylococcus aureus
Membrane Potentials
Cell Wall
Genes
Electron Microscopy
Down-Regulation
Gene Expression
Pharmaceutical Preparations
Proteins

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

Cite this

Serial daptomycin selection generates daptomycin-nonsusceptible Staphylococcus aureus strains with a heterogeneous vancomycin-intermediate phenotype. / Camargo, Ilana Lopes Baratella Da Cunha; Neoh, Hui Min; Cui, Longzhu; Hiramatsu, Keiichi.

In: Antimicrobial Agents and Chemotherapy, Vol. 52, No. 12, 12.2008, p. 4289-4299.

Research output: Contribution to journalArticle

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