Daptomycin-Resistant Enterococcus faecalis Diverts the Antibiotic Molecule from the Division Septum and Remodels Cell Membrane Phospholipids

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dc.citation.firstpagee00281-13en_US
dc.citation.issueNumber4en_US
dc.citation.journalTitlemBioen_US
dc.citation.volumeNumber4en_US
dc.contributor.authorTran, Truc T.en_US
dc.contributor.authorPanesso, Dianaen_US
dc.contributor.authorMishra, Nagendra N.en_US
dc.contributor.authorMileykovskaya, Eugeniaen_US
dc.contributor.authorGuan, Ziqiangen_US
dc.contributor.authorMunita, Jose M.en_US
dc.contributor.authorReyes, Jinnetheen_US
dc.contributor.authorDiaz, Lorenaen_US
dc.contributor.authorWeinstock, George M.en_US
dc.contributor.authorMurray, Barbara E.en_US
dc.contributor.authorShamoo, Yousifen_US
dc.contributor.authorDowhan, Williamen_US
dc.contributor.authorBayer, Arnold S.en_US
dc.contributor.authorArias, Cesar A.en_US
dc.date.accessioned2013-08-02T16:01:31Zen_US
dc.date.available2013-08-02T16:01:31Zen_US
dc.date.issued2013en_US
dc.description.abstractTreatment of multidrug-resistant enterococci has become a challenging clinical problem in hospitals around the world due to the lack of reliable therapeutic options. Daptomycin (DAP), a cell membrane-targeting cationic antimicrobial lipopeptide, is the only antibiotic with in vitro bactericidal activity against vancomycin-resistant enterococci (VRE). However, the clinical use of DAP against VRE is threatened by emergence of resistance during therapy, but the mechanisms leading to DAP resistance are not fully understood. The mechanism of action of DAP involves interactions with the cell membrane in a calciumdependent manner, mainly at the level of the bacterial septum. Previously, we demonstrated that development of DAP resistance in vancomycin-resistant Enterococcus faecalis is associated with mutations in genes encoding proteins with two main functions, (i) control of the cell envelope stress response to antibiotics and antimicrobial peptides (LiaFSR system) and (ii) cell membrane phospholipid metabolism (glycerophosphoryl diester phosphodiesterase and cardiolipin synthase). In this work, we show that these VRE can resist DAP-elicited cell membrane damage by diverting the antibiotic away from its principal target (division septum) to other distinct cell membrane regions. DAP septal diversion by DAP-resistant E. faecalis is mediated by initial redistribution of cell membrane cardiolipin-rich microdomains associated with a single amino acid deletion within the transmembrane protein LiaF (a member of a three-component regulatory system [LiaFSR] involved in cell envelope homeostasis). Full expression of DAP resistance requires additional mutations in enzymes (glycerophosphoryl diester phosphodiesterase and cardiolipin synthase) that alter cell membrane phospholipid content. Our findings describe a novel mechanism of bacterial resistance to cationic antimicrobial peptides.en_US
dc.embargo.termsnoneen_US
dc.identifier.citationTran, Truc T., Panesso, Diana, Mishra, Nagendra N., et al.. "Daptomycin-Resistant Enterococcus faecalis Diverts the Antibiotic Molecule from the Division Septum and Remodels Cell Membrane Phospholipids." <i>mBio,</i> 4, no. 4 (2013) American Society for Microbiology: e00281-13. http://dx.doi.org/10.1128/mBio.00281-13.en_US
dc.identifier.doihttp://dx.doi.org/10.1128/mBio.00281-13en_US
dc.identifier.urihttps://hdl.handle.net/1911/71721en_US
dc.language.isoengen_US
dc.publisherAmerican Society for Microbiologyen_US
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.rights.urihttps://creativecommons.org/licenses/by-nc-sa/3.0/en_US
dc.titleDaptomycin-Resistant Enterococcus faecalis Diverts the Antibiotic Molecule from the Division Septum and Remodels Cell Membrane Phospholipidsen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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