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Whole genome characterization of the mechanisms of daptomycin resistance in clinical and laboratory derived isolates of Staphylococcus aureus

Journal Article


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Abstract


  • Background

    Daptomycin remains one of our last-line anti-staphylococcal agents. This study aims to characterize the genetic evolution to daptomycin resistance in S. aureus.

    Methods

    Whole genome sequencing was performed on a unique collection of isogenic, clinical (21 strains) and laboratory (12 strains) derived strains that had been exposed to daptomycin and developed daptomycin-nonsusceptibility. Electron microscopy (EM) and lipid membrane studies were performed on selected isolates.

    Results

    On average, six coding region mutations were observed across the genome in the clinical daptomycin exposed strains, whereas only two mutations on average were seen in the laboratory exposed pairs. All daptomycin-nonsusceptible strains had a mutation in a phospholipid biosynthesis gene. This included mutations in the previously described mprF gene, but also in other phospholipid biosynthesis genes, including cardiolipin synthase (cls2) and CDP-diacylglycerol-glycerol-3-phosphate 3-phosphatidyltransferase (pgsA). EM and lipid membrane composition analyses on two clinical pairs showed that the daptomycin-nonsusceptible strains had a thicker cell wall and an increase in membrane lysyl-phosphatidylglycerol.

    Conclusion

    Point mutations in genes coding for membrane phospholipids are associated with the development of reduced susceptibility to daptomycin in S. aureus. Mutations in cls2 and pgsA appear to be new genetic mechanisms affecting daptomycin susceptibility in S. aureus.

UOW Authors


  •   Peleg, Anton Y. (external author)
  •   Miyakis, Spiros
  •   Ward, Doyle V. (external author)
  •   Earl, Ashlee M. (external author)
  •   Rubio, Aileen (external author)
  •   Cameron, David R. (external author)
  •   Pillai, Satish K. (external author)
  •   Moellering, Robert C. (external author)
  •   Eliopoulos, George M. (external author)

Publication Date


  • 2012

Citation


  • Peleg, A. Y., Miyakis, S., Ward, D. V., Earl, A. M., Rubio, A., Cameron, D. R., Pillai, S., Moellering, R. C. & Eliopoulos, G. M. (2012). Whole genome characterization of the mechanisms of daptomycin resistance in clinical and laboratory derived isolates of Staphylococcus aureus. PLoS One, 7 (1), e28316.

Scopus Eid


  • 2-s2.0-84855416641

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1561&context=medpapers

Ro Metadata Url


  • http://ro.uow.edu.au/medpapers/557

Has Global Citation Frequency


Start Page


  • e28316

Volume


  • 7

Issue


  • 1

Place Of Publication


  • United States

Abstract


  • Background

    Daptomycin remains one of our last-line anti-staphylococcal agents. This study aims to characterize the genetic evolution to daptomycin resistance in S. aureus.

    Methods

    Whole genome sequencing was performed on a unique collection of isogenic, clinical (21 strains) and laboratory (12 strains) derived strains that had been exposed to daptomycin and developed daptomycin-nonsusceptibility. Electron microscopy (EM) and lipid membrane studies were performed on selected isolates.

    Results

    On average, six coding region mutations were observed across the genome in the clinical daptomycin exposed strains, whereas only two mutations on average were seen in the laboratory exposed pairs. All daptomycin-nonsusceptible strains had a mutation in a phospholipid biosynthesis gene. This included mutations in the previously described mprF gene, but also in other phospholipid biosynthesis genes, including cardiolipin synthase (cls2) and CDP-diacylglycerol-glycerol-3-phosphate 3-phosphatidyltransferase (pgsA). EM and lipid membrane composition analyses on two clinical pairs showed that the daptomycin-nonsusceptible strains had a thicker cell wall and an increase in membrane lysyl-phosphatidylglycerol.

    Conclusion

    Point mutations in genes coding for membrane phospholipids are associated with the development of reduced susceptibility to daptomycin in S. aureus. Mutations in cls2 and pgsA appear to be new genetic mechanisms affecting daptomycin susceptibility in S. aureus.

UOW Authors


  •   Peleg, Anton Y. (external author)
  •   Miyakis, Spiros
  •   Ward, Doyle V. (external author)
  •   Earl, Ashlee M. (external author)
  •   Rubio, Aileen (external author)
  •   Cameron, David R. (external author)
  •   Pillai, Satish K. (external author)
  •   Moellering, Robert C. (external author)
  •   Eliopoulos, George M. (external author)

Publication Date


  • 2012

Citation


  • Peleg, A. Y., Miyakis, S., Ward, D. V., Earl, A. M., Rubio, A., Cameron, D. R., Pillai, S., Moellering, R. C. & Eliopoulos, G. M. (2012). Whole genome characterization of the mechanisms of daptomycin resistance in clinical and laboratory derived isolates of Staphylococcus aureus. PLoS One, 7 (1), e28316.

Scopus Eid


  • 2-s2.0-84855416641

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1561&context=medpapers

Ro Metadata Url


  • http://ro.uow.edu.au/medpapers/557

Has Global Citation Frequency


Start Page


  • e28316

Volume


  • 7

Issue


  • 1

Place Of Publication


  • United States