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Two Mutations Commonly Associated with Daptomycin Resistance in Enterococcus faecium LiaST120A and LiaRW73C Appear To

Milya Davlieva1, Chelsea Wu1, Yue Zhou1

  • 1Department of Biosciences , Rice University , Houston , Texas 77005 , United States.

Biochemistry
|November 8, 2018
PubMed

Insights

Daptomycin resistance in Enterococcus faecium involves the LiaFSR pathway. Specific mutations in LiaS and LiaR enhance this pathway, increasing resistance. Understanding these interactions could lead to new therapies against resistant infections.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Drug Resistance

Background:

  • Daptomycin is crucial for treating multidrug-resistant Enterococcus faecium infections.
  • Resistance often arises from the LiaFSR membrane stress response pathway.
  • Identifying resistance mechanisms is key to developing effective treatments.

Purpose of the Study:

  • Investigate the epistatic relationship between LiaS and LiaR mutations in daptomycin resistance.
  • Characterize the in vitro biochemical behavior of these resistance-associated mutations.
  • Explore the LiaFSR pathway as a potential drug target.

Main Methods:

  • In vitro phosphorylation assays to study protein interactions.
  • Analysis of phosphotransfer and dephosphorylation rates.
  • Examination of LiaS-LiaR interactions in the presence of specific mutations.

Main Results:

  • LiaST120A mutation increases LiaRW73C dephosphorylation.
  • Combined LiaST120A and LiaRW73C mutations enhance LiaFSR signaling.
  • This coordinated effect decreases daptomycin susceptibility in E. faecium.

Conclusions:

  • The LiaST120A and LiaRW73C mutations work together to strengthen LiaFSR signaling, promoting daptomycin resistance.
  • The developed in vitro methods can screen for inhibitors of the LiaFSR pathway.
  • Targeting the LiaFSR pathway offers a strategy to combat daptomycin resistance.

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