Daptomycin Resistance in Enterococci Is Associated with Distinct Alterations of Cell Membrane Phospholipid Content

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dc.citation.firstpagee43958en_US
dc.citation.issueNumber8en_US
dc.citation.journalTitlePLoS ONEen_US
dc.citation.volumeNumber7en_US
dc.contributor.authorMishra, Nagendra N.en_US
dc.contributor.authorBayer, Arnold S.en_US
dc.contributor.authorTran, Truc T.en_US
dc.contributor.authorShamoo, Yousifen_US
dc.contributor.authorMileykovskaya, Eugeniaen_US
dc.contributor.authorDowhan, Williamen_US
dc.contributor.authorGuan, Ziqiangen_US
dc.contributor.authorArias, Cesar A.en_US
dc.date.accessioned2016-01-29T21:44:39Zen_US
dc.date.available2016-01-29T21:44:39Zen_US
dc.date.issued2012en_US
dc.description.abstractBackground: The lipopeptide antibiotic, daptomycin (DAP) interacts with the bacterial cell membrane (CM). Development of DAP resistance during therapy in a clinical strain of Enterococcus faecalis was associated with mutations in genes encoding enzymes involved in cell envelope homeostasis and phospholipid metabolism. Here we characterized changes in CM phospholipid profiles associated with development of DAP resistance in clinical enterococcal strains. Methodology: Using two clinical strain-pairs of DAP-susceptible and DAP-resistant E. faecalis (S613 vs. R712) and E. faecium (S447 vs. R446) recovered before and after DAP therapy, we compared four distinct CM profiles: phospholipid content, fatty acid composition, membrane fluidity and capacity to be permeabilized and/or depolarized by DAP. Additionally, we characterized the cell envelope of the E. faecium strain-pair by transmission electron microscopy and determined the relative cell surface charge of both strain-pairs. Principal Findings: Both E. faecalis and E. faecium mainly contained four major CM PLs: phosphatidylglycerol (PG), cardiolipin, lysyl-phosphatidylglycerol (L-PG) and glycerolphospho-diglycodiacylglycerol (GP-DGDAG). In addition, E. faecalis CMs (but not E. faecium) also contained: i) phosphatidic acid; and ii) two other unknown species of amino-containing PLs. Development of DAP resistance in both enterococcal species was associated with a significant decrease in CM fluidity and PG content, with a concomitant increase in GP-DGDAG. The strain-pairs did not differ in their outer CM translocation (flipping) of amino-containing PLs. Fatty acid content did not change in the E. faecalis strain-pair, whereas a significant decrease in unsaturated fatty acids was observed in the DAP-resistant E. faecium isolate R446 (vs S447). Resistance to DAP in E. faecium was associated with distinct structural alterations of the cell envelope and cell wall thickening, as well as a decreased ability of DAP to depolarize and permeabilize the CM. Conclusion: Distinct alterations in PL content and fatty acid composition are associated with development of enterococcal DAP resistance.en_US
dc.identifier.citationMishra, Nagendra N., Bayer, Arnold S., Tran, Truc T., et al.. "Daptomycin Resistance in Enterococci Is Associated with Distinct Alterations of Cell Membrane Phospholipid Content." <i>PLoS ONE,</i> 7, no. 8 (2012) Public Library of Science: e43958. http://dx.doi.org/10.1371/journal.pone.0043958.en_US
dc.identifier.doihttp://dx.doi.org/10.1371/journal.pone.0043958en_US
dc.identifier.urihttps://hdl.handle.net/1911/88285en_US
dc.language.isoengen_US
dc.publisherPublic Library of Scienceen_US
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.titleDaptomycin Resistance in Enterococci Is Associated with Distinct Alterations of Cell Membrane Phospholipid Contenten_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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