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Nanomechanics of Drug-target Interactions and Antibacterial Resistance Detection
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Molecular basis of cell membrane adaptation in daptomycin-resistant Enterococcus faecalis

April H Nguyen1,2,3, Truc T Tran2,3,4, Diana Panesso2,3,4,5

  • 1Department of Microbiology and Molecular Genetics, University of Texas Health Science Center, Houston, Texas, USA.

JCI Insight
|October 15, 2024
PubMed

Insights

Enterococcus faecalis resists daptomycin by altering its cell membrane (CM). This study reveals cardiolipin synthase (Cls) and LiaY are key to CM remodeling and daptomycin resistance.

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.
Keywords:
Bacterial infectionsInfectious diseaseLipid raftsPeptides

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