A variable DNA recognition site organization establishes the Liar-mediated cell envelope stress response of enterococci to daptomycin

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dc.contributor.authorDavlieva, Milya
dc.contributor.authorShi, Yiwen
dc.contributor.authorLeonard, Paul G.
dc.contributor.authorJohnson, Troy A.
dc.contributor.authorZianni, Michael R.
dc.contributor.authorArias, Cesar A.
dc.contributor.authorLadbury, John E.
dc.contributor.authorShamoo, Yousif
dc.date.accessioned2019-09-11T19:15:23Z
dc.date.available2019-09-11T19:15:23Z
dc.date.issued2015
dc.description.abstractenglishLiaR is a ‘master regulator’ of the cell envelope stress response in enterococci and many other Gram-positive organisms. Mutations to liaR can lead to antibiotic resistance to a variety of antibiotics including the cyclic lipopeptide daptomycin. LiaR is phosphorylated in response to membrane stress to regulate downstream target operons. Using DNA footprinting of the regions upstream of the liaXYZ and liaFSR operons we show that LiaR binds an extended stretch of DNA that extends beyond the proposed canonical consensus sequence suggesting a more complex level of regulatory control of target operons. We go on to determine the biochemical and structural basis for increased resistance to daptomycin by the adaptive mutation to LiaR (D191N) first identified from the pathogen Enterococcus faecalis S613. LiaRD191N increases oligomerization of LiaR to form a constitutively activated tetramer that has high affinity for DNA even in the absence of phosphorylation leading to increased resistance. Crystal structures of the LiaR DNA binding domain complexed to the putative consensus sequence as well as an adjoining secondary sequence show that upon binding, LiaR induces DNA bending that is consistent with increased recruitment of RNA polymerase to the transcription start site and upregulation of target operons.eng
dc.format.mimetypeapplication/pdf
dc.identifier.doihttps://doi.org/10.1093/nar/gkv321
dc.identifier.instnameinstname:Universidad El Bosquespa
dc.identifier.issn1362-4962
dc.identifier.reponamereponame:Repositorio Institucional Universidad El Bosquespa
dc.identifier.repourlrepourl:https://repositorio.unbosque.edu.co
dc.identifier.urihttps://hdl.handle.net/20.500.12495/1668
dc.language.isoeng
dc.publisherOxford University Pressspa
dc.publisher.journalNucleic Acids Researchspa
dc.relation.ispartofseriesNucleic Acids Research, 0305-1048, Vol. 43, Nro, 9, 2015, p. 4758-4773spa
dc.relation.urihttps://academic.oup.com/nar/article/43/9/4758/1122836
dc.rightsAttribution-NonCommercial 4.0 International*
dc.rights.accessrightsinfo:eu-repo/semantics/openAccess
dc.rights.accessrightshttps://purl.org/coar/access_right/c_abf387
dc.rights.creativecommons2015
dc.rights.localAcceso abiertospa
dc.rights.urihttps://creativecommons.org/licenses/by-nc/4.0/*
dc.subject.decsFarmacorresistencia microbianaspa
dc.subject.decsDaptomicinaspa
dc.subject.decsEnterococcus faecalisspa
dc.titleA variable DNA recognition site organization establishes the Liar-mediated cell envelope stress response of enterococci to daptomycinspa
dc.typearticlespa
dc.type.hasversioninfo:eu-repo/semantics/publishedVersion
dc.type.localartículospa

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