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

摘要: The lipopeptide antibiotic daptomycin (DAP) is a key drug against serious enterococcal infections, but the emergence of resistance in clinical setting major concern. LiaFSR system plays prominent role development DAP (DAP-R) enterococci, and blocking this stress response has been proposed as novel therapeutic strategy. In work, we identify LiaR-independent pathways Enterococcus faecalis that regulate cell membrane adaptation to antibiotics. We adapted E. OG1RF (a laboratory strain) S613TM lacking liaR increasing concentrations DAP, leading DAP-R elevated MICs bacitracin ceftriaxone. Whole genome sequencing identified changes YxdJK two-component regulatory putative fatty acid kinase (dak) both strains. Deletion gene encoding YxdJ regulator mutant wild-type decreased even when functional was present. Mutations dak were associated with slower growth, fluidity alterations morphology. These findings suggest overlapping can provide protection antimicrobial peptides at significant cost bacterial fitness.