Mechanisms of daptomycin resistance in Staphylococcus aureus: role of the cell membrane and cell wall

Authors

  • Arnold S. Bayer,

    1. Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles, Torrance, California.
    2. David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California.
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  • Tanja Schneider,

    1. Institute of Medical Microbiology, Immunology and Parasitology-Pharmaceutical Microbiology Section, University of Bonn, Bonn, Germany
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  • Hans-Georg Sahl

    1. Institute of Medical Microbiology, Immunology and Parasitology-Pharmaceutical Microbiology Section, University of Bonn, Bonn, Germany
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Arnold S. Bayer, LA Biomedical Research Institute, 1124 West Carson St, Bldg RB2-Room 225, Torrance, CA 905092. abayer@labiomed.org

Abstract

The bactericidal, cell membrane–targeting lipopeptide antibiotic daptomycin (DAP) is an important agent in treating invasive Staphylococcus aureus infections. However, there have been numerous recent reports of development of daptomycin resistance (DAP-R) during therapy with this agent. The mechanisms of DAP-R in S. aureus appear to be quite diverse. DAP-R strains often exhibit progressive accumulation of single nucleotide polymorphisms in the multipeptide resistance factor gene (mprF) and the yycFG components of the yycFGHI operon. Both loci are involved in key cell membrane (CM) events, with mprF being responsible for the synthesis and outer CM translocation of the positively charged phospholipid, lysyl-phosphotidylglycerol (L-PG), while the yyc operon is involved in the generalized response to stressors such as antimicrobials. In addition, other perturbations of the CM have been identified in DAP-R strains, including extremes in CM order, resistance to CM depolarization and permeabilization, and reduced surface binding of DAP. Moreover, modifications of the cell wall (CW) appear to also contribute to DAP-R, including enhanced expression of the dlt operon (involved in d-alanylation of CW teichoic acids) and progressive CW thickening.

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