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

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

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.

Más información

Título según WOS: ID WOS:000461081000017 Not found in local WOS DB
Título de la Revista: MOLECULAR MICROBIOLOGY
Volumen: 111
Número: 3
Editorial: Wiley
Fecha de publicación: 2019
Página de inicio: 811
Página final: 824
DOI:

10.1111/mmi.14193

Notas: ISI