LiaR-independent pathways to daptomycin resistance in Enterococcus faecalis reveal a multilayer defense against cell envelope antibiotics

William R. Miller, Truc T. Tran, Lorena Diaz, Rafael Rios, Ayesha Khan, Jinnethe Reyes, Amy G. Prater, Diana Panesso, Yousif Shamoo, Cesar A. Arias

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

The 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 fitness.

Original languageEnglish (US)
Pages (from-to)811-824
Number of pages14
JournalMolecular Microbiology
Volume111
Issue number3
DOIs
StatePublished - Mar 2019

ASJC Scopus subject areas

  • Microbiology
  • Molecular Biology

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