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dc.contributor.authorTran, Truc T.
Panesso, Diana
Mishra, Nagendra N.
Mileykovskaya, Eugenia
Guan, Ziqianq
Munita, Jose M.
Reyes, Jinnethe
Diaz, Lorena
Weinstock, George M.
Murray, Barbara E.
Shamoo, Yousif
Dowhan, William
Bayer, Arnold S.
Arias, Cesar A.
dc.date.accessioned 2013-08-02T16:01:31Z
dc.date.available 2013-08-02T16:01:31Z
dc.date.issued 2013
dc.identifier.citation Tran, 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." mBio, 4, no. 4 (2013) American Society for Microbiology: e00281-13. http://dx.doi.org/10.1128/mBio.00281-13.
dc.identifier.urihttps://hdl.handle.net/1911/71721
dc.description.abstract Treatment 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.
dc.language.iso eng
dc.publisher American Society for Microbiology
dc.rights This 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.
dc.rights.urihttps://creativecommons.org/licenses/by-nc-sa/3.0/
dc.title Daptomycin-Resistant Enterococcus faecalis Diverts the Antibiotic Molecule from the Division Septum and Remodels Cell Membrane Phospholipids
dc.type Journal article
dc.citation.journalTitle mBio
dc.citation.volumeNumber 4
dc.citation.issueNumber 4
dc.embargo.terms none
dc.type.dcmi Text
dc.identifier.doihttp://dx.doi.org/10.1128/mBio.00281-13
dc.identifier.pmcid PMC3735187
dc.identifier.pmid 23882013
dc.type.publication publisher version
dc.citation.firstpage e00281-13


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