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Whole-genome analysis of a daptomycin-susceptible enterococcus faecium strain and its daptomycin-resistant variant

Truc T Tran1, Diana Panesso, Hongyu Gao

  • 1Department of Internal Medicine, Division of Infectious Diseases, University of Houston College of Pharmacy, Houston, Texas, USA.

Antimicrobial Agents and Chemotherapy
|November 2, 2012
PubMed

Insights

Daptomycin resistance in Enterococcus faecium is linked to mutations in cell membrane phospholipid metabolism and the YycFG system. This study identifies key genetic changes mediating resistance in clinical strains.

Area of Science:

  • Microbiology
  • Genetics
  • Molecular Biology

Background:

  • Daptomycin (DAP) resistance in Enterococcus faecalis involves mutations in cell envelope stress response and phospholipid metabolism.
  • The genetic mechanisms of DAP resistance in Enterococcus faecium remain largely unknown.

Purpose of the Study:

  • To elucidate the genetic basis of daptomycin resistance in Enterococcus faecium.
  • To compare whole-genome sequences of DAP-susceptible and DAP-resistant clinical strains of E. faecium.

Main Methods:

  • Whole-genome comparative analysis of a clinical strain pair (DAP-susceptible E. faecium S447 and DAP-resistant E. faecium R446).
  • Identification of genetic mutations associated with DAP resistance in the derivative strain.

Main Results:

  • Daptomycin resistance in E. faecium R446 was associated with mutations in 8 genes.
  • Key mutations included substitutions in cardiolipin synthase (cls) and the YycFG system's histidine kinase (YycG).
  • Genetic exchange of the cls allele did not alter DAP susceptibility, suggesting other mechanisms are primary.

Conclusions:

  • The YycFG system, in addition to the LiaFSR system, is likely a significant mediator of daptomycin resistance in certain Enterococcus faecium strains.
  • Mutations in phospholipid metabolism and cell envelope homeostasis pathways are critical for DAP resistance development.

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