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dc.contributor.authorMiller, William R.
dc.contributor.authorTran, Truc T.
dc.contributor.authorDiaz, Lorena
dc.contributor.authorRios, Rafael
dc.contributor.authorKhan, Ayesha
dc.contributor.authorReyes, Jinnethe
dc.contributor.authorPrater, Amy G.
dc.contributor.authorPanesso, Diana
dc.contributor.authorShamoo, Yousif
dc.contributor.authorArias, Cesar A.
dc.relation.ispartofseriesMolecular microbiology, 0950-382X, Vol 111, Num 3, 2019, pag 811-824spa
dc.titleLiaR‐independent pathways to daptomycin resistance in enterococcus faecalis reveal a multilayer defense against cell envelope antibioticsspa
dc.publisher.journalMolecular microbiologyspa
dc.title.translatedLiaR‐independent pathways to daptomycin resistance in enterococcus faecalis reveal a multilayer defense against cell envelope antibioticsspa
dc.description.abstractenglishThe lipopeptide antibiotic daptomycin (DAP) is a key drug against serious enterococcal infections, but the emergence of resistance in the clinical setting is a major concern. The LiaFSR system plays a prominent role in the development of DAP resistance (DAP‐R) in enterococci, and blocking this stress response system has been proposed as a novel therapeutic strategy. In this work, we identify LiaR‐independent pathways in Enterococcus faecalis that regulate cell membrane adaptation in response to antibiotics. We adapted E. faecalis OG1RF (a laboratory strain) and S613TM (a clinical strain) lacking liaR to increasing concentrations of DAP, leading to the development of DAP‐R and elevated MICs to bacitracin and ceftriaxone. Whole genome sequencing identified changes in the YxdJK two‐component regulatory system and a putative fatty acid kinase (dak) in both DAP‐R strains. Deletion of the gene encoding the YxdJ response regulator in both the DAP‐R mutant and wild‐type OG1RF decreased MICs to DAP, even when a functional LiaFSR system was present. Mutations in dak were associated with slower growth, decreased membrane fluidity and alterations of cell morphology. These findings suggest that overlapping stress response pathways can provide protection against antimicrobial peptides in E. faecalis at a significant cost in bacterial
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