Deletion of liaR Reverses Daptomycin Resistance in Enterococcus faecium Independent of the Genetic Background

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dc.citation.firstpage7327en_US
dc.citation.issueNumber12en_US
dc.citation.journalTitleAntimicrobial Agents and Chemotherapyen_US
dc.citation.lastpage7334en_US
dc.citation.volumeNumber59en_US
dc.contributor.authorPanesso, Dianaen_US
dc.contributor.authorReyes, Jinnetheen_US
dc.contributor.authorGaston, Elizabethen_US
dc.contributor.authorDeal, Morganen_US
dc.contributor.authorLondoño, Alejandraen_US
dc.contributor.authorNigo, Masayukien_US
dc.contributor.authorMunita, Jose M.en_US
dc.contributor.authorMiller, William R.en_US
dc.contributor.authorShamoo, Yousifen_US
dc.contributor.authorTran, Truc T.en_US
dc.contributor.authorArias, Cesar A.en_US
dc.date.accessioned2016-01-19T19:19:42Zen_US
dc.date.available2016-01-19T19:19:42Zen_US
dc.date.issued2015en_US
dc.description.abstractWe have shown previously that changes in LiaFSR, a three-component regulatory system predicted to orchestrate the cell membrane stress response, are important mediators of daptomycin (DAP) resistance in enterococci. Indeed, deletion of the gene encoding the response regulator LiaR in a clinical strain of Enterococcus faecalis reversed DAP resistance (DAP-R) and produced a strain hypersusceptible to antimicrobial peptides. Since LiaFSR is conserved in Enterococcus faecium, we investigated the role of LiaR in a variety of clinical E. faecium strains representing the most common DAP-R genetic backgrounds. Deletion of liaR in DAP-R E. faecium R446F (DAP MIC of 16 μg/ml) and R497F (MIC of 24 μg/ml; harboring changes in LiaRS) strains fully reversed resistance (DAP MICs decreasing to 0.25 and 0.094 μg/ml, respectively). Moreover, DAP at concentrations of 13 μg/ml (achieved with human doses of 12 mg/kg body weight) retained bactericidal activity against the mutants. Furthermore, the liaR deletion derivatives of these two DAP-R strains exhibited increased binding of boron-dipyrromethene difluoride (BODIPY)-daptomycin, suggesting that high-level DAP-R mediated by LiaR in E. faecium involves repulsion of the calcium-DAP complex from the cell surface. In DAP-tolerant strains HOU503F and HOU515F (DAP MICs within the susceptible range but bacteria not killed by DAP concentrations of 5× the MIC), deletion of liaRnot only markedly decreased the DAP MICs (0.064 and 0.047 μg/ml, respectively) but also restored the bactericidal activity of DAP at concentrations as low as 4 μg/ml (achieved with human doses of 4 mg/kg). Our results suggest that LiaR plays a relevant role in the enterococcal cell membrane adaptive response to antimicrobial peptides independent of the genetic background and emerges as an attractive target to restore the activity of DAP against multidrug-resistant strains.en_US
dc.identifier.citationPanesso, Diana, Reyes, Jinnethe, Gaston, Elizabeth, et al.. "Deletion of liaR Reverses Daptomycin Resistance in Enterococcus faecium Independent of the Genetic Background." <i>Antimicrobial Agents and Chemotherapy,</i> 59, no. 12 (2015) American Society for Microbiology: 7327-7334. http://dx.doi.org/10.1128/AAC.01073-15.en_US
dc.identifier.doihttp://dx.doi.org/10.1128/AAC.01073-15en_US
dc.identifier.urihttps://hdl.handle.net/1911/87884en_US
dc.language.isoengen_US
dc.publisherAmerican Society for Microbiologyen_US
dc.rightsThis is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by the American Society for Microbiology.en_US
dc.titleDeletion of liaR Reverses Daptomycin Resistance in Enterococcus faecium Independent of the Genetic Backgrounden_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpost-printen_US
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