Molecular Basis of Cell Membrane Adaptation in Daptomycin-Resistant Enterococcus faecalis

Area of Science:

• Microbiology
• Molecular Biology
• Biochemistry

Background:

• Daptomycin is a critical antibiotic for treating Gram-positive bacterial infections.
• Enterococcus faecalis exhibits resistance to daptomycin through cell membrane (CM) remodeling.
• The LiaFSR system and cardiolipin synthase (Cls) are implicated in this resistance, but their roles are unclear.

Approach:

• Investigated the role of cardiolipin synthase (Cls) in daptomycin resistance.
• Examined the function of the LiaFSR regulatory system and LiaY protein in CM remodeling.
• Utilized gene deletion strategies to assess the necessity of Cls activity and LiaY.

Key Points:

• Cardiolipin synthase activity is essential for anionic phospholipid redistribution and daptomycin resistance in E. faecalis.
• Deletion of cardiolipin synthase genes (cls1 and cls2) abrogated CM remodeling.
• LiaY, a LiaFSR-regulated transmembrane protein, mediates CM remodeling through interaction with Cls1.

Conclusions:

• Cardiolipin synthase activity is indispensable for the enterococcal daptomycin resistance mechanism.
• LiaY acts as a key mediator in the LiaFSR-controlled CM response.
• This study elucidates a mechanistic framework for enterococcal antibiotic resistance, offering potential therapeutic targets.