Molecular basis of cell membrane adaptation in daptomycin-resistant Enterococcus faecalis

Area of Science:

• Microbiology
• Molecular Biology
• Antibiotic Resistance

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 mechanism.

Purpose of the Study:

• To elucidate the mechanism by which LiaFSR regulates CM response to daptomycin.
• To determine the specific role of cardiolipin synthase (Cls) in daptomycin resistance.
• To identify key mediators of CM remodeling in Enterococcus faecalis.

Main Methods:

• Gene deletion studies of cls1 and cls2 to assess the role of cardiolipin synthase.
• Identification of transmembrane protein LiaY and its regulation by LiaFSR.
• Analysis of CM anionic phospholipid redistribution and its impact on daptomycin resistance.

Main Results:

• Cardiolipin synthase activity is essential for anionic phospholipid redistribution and daptomycin resistance.
• Deletion of cls1 and cls2 genes abolished CM remodeling, rendering bacteria sensitive to daptomycin.
• LiaY and Cls1 were identified as crucial mediators of CM remodeling and anionic phospholipid microdomain redistribution.

Conclusions:

• Cardiolipin synthase is vital for Enterococcus faecalis to resist daptomycin.
• LiaY and Cls1 orchestrate the cell membrane response, enabling resistance.
• This mechanistic framework offers potential therapeutic targets for combating antibiotic resistance.