Phenotypic and Genotypic Characterization of Daptomycin-Resistant Methicillin-Resistant Staphylococcus aureus Strains: Relative Roles of mprF and dlt Operons

PLoS One

Soo-Jin Yang¹  Michael R. Yeaman¹  Cynthia C. Nast¹  Nagendra N. Mishra²  Christopher Weidenmaier²  Stefania Stefani³  Viviana Cafiso⁴  Taschia Bertuccio⁴  Stefanie Wanner⁴  Arnold S. Bayer⁵  Timo Grau⁵ 

[1] Department of Biomedical Sciences-Microbiology, University of Catania, Catania, Italy;Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America;German Center for Infection Research (DZIF), Tübingen, Germany;Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, Tübingen, Germany;The David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America

关键词: Fatty acids;    Staphylococcus aureus;    Methicillin-resistant Staphylococcus aureus;    Cell walls;    Cell membranes;    Phospholipids;    RNA isolation;    Phenotypes;   

DOI  :  10.1371/journal.pone.0107426

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

Development of in vivo daptomycin resistance (DAP-R) among Staphylococcus aureus clinical isolates, in association with clinical treatment failures, has become a major therapeutic problem. This issue is especially relevant to methicillin-resistant S. aureus (MRSA) strains in the context of invasive endovascular infections. In the current study, we used three well-characterized and clinically-derived DAP-susceptible (DAP-S) vs. resistant (DAP-R) MRSA strain-pairs to elucidate potential genotypic mechanisms of the DAP-R phenotype. In comparison to the DAP-S parental strains, DAP-R isolates demonstrated (i) altered expression of two key determinants of net positive surface charge, either during exponential or stationary growth phases (i.e., dysregulation of dltA and mprF), (ii) a significant increase in the D-alanylated wall teichoic acid (WTA) content in DAP-R strains, reflecting DltA gain-in-function; (iii) heightened elaboration of lysinylated-phosphatidylglyderol (L-PG) in DAP-R strains, reflecting MprF gain-in-function; (iv) increased cell membrane (CM) fluidity, and (v) significantly reduced susceptibility to prototypic cationic host defense peptides of platelet and leukocyte origins. In the tested DAP-R strains, genes conferring positive surface charge were dysregulated, and their functionality altered. However, there were no correlations between relative surface positive charge or cell wall thickness and the observed DAP-R phenotype. Thus, charge repulsion mechanisms via altered surface charge may not be sufficient to explain the DAP-R outcome. Instead, changes in the compositional or biophysical order of the DAP CM target of such DAP-R strains (i.e., increased fluidity) may be essential to this phenotype. Taken together, DAP-R in S. aureus appears to involve multi-factorial and strain-specific adaptive mechanisms.

【 授权许可】

CC BY