Daptomycin-resistant enterococcus faecalis diverts the antibiotic molecule from the division septum and remodels cell membrane phospholipids

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dc.contributor.authorTran, Truc T.
dc.contributor.authorPanesso, Diana
dc.contributor.authorMishra, Nagendra N.
dc.contributor.authorMileykovskaya, Eugenia
dc.contributor.authorGuan, Ziqianq
dc.contributor.authorMunita, José M.
dc.contributor.authorReyes, Jinnethe
dc.contributor.authorDíaz, Lorena
dc.contributor.authorWeinstock, George M.
dc.contributor.authorMurray, Barbara E
dc.contributor.authorShamoo, Yousif
dc.contributor.authorDowhan, William
dc.contributor.authorBayer, Arnold S.
dc.contributor.authorArias, César A.
dc.contributor.orcidPanesso, Diana [0000-0002-4049-9702]
dc.date.accessioned2019-09-12T21:21:37Z
dc.date.available2019-09-12T21:21:37Z
dc.date.issued2013
dc.description.abstractenglishTreatment 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.eng
dc.format.mimetypeapplication/pdf
dc.identifier.doihttps://doi.org/10.1128/mBio.00281-13
dc.identifier.instnameinstname:Universidad El Bosquespa
dc.identifier.issn2150-7511
dc.identifier.reponamereponame:Repositorio Institucional Universidad El Bosquespa
dc.identifier.repourlrepourl:https://repositorio.unbosque.edu.co
dc.identifier.urihttps://hdl.handle.net/20.500.12495/1674
dc.language.isoeng
dc.publisherAmerican Society for Microbiologyspa
dc.publisher.journalmBiospa
dc.relation.ispartofseriesmBio, 2150-7511, Vol. 4, Nro. 4, 2013.spa
dc.relation.urihttps://mbio.asm.org/content/4/4/e00281-13.short
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.rights.accessrightsinfo:eu-repo/semantics/openAccess
dc.rights.accessrightshttps://purl.org/coar/access_right/c_abf327
dc.rights.creativecommons2013
dc.rights.localAcceso abiertospa
dc.rights.urihttps://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subject.decsFarmacorresistencia microbianaspa
dc.subject.decsVancomicinaspa
dc.subject.decsDaptomicinaspa
dc.titleDaptomycin-resistant enterococcus faecalis diverts the antibiotic molecule from the division septum and remodels cell membrane phospholipidsspa
dc.typearticlespa
dc.type.hasversioninfo:eu-repo/semantics/publishedVersion
dc.type.localartículospa

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