| Autor: |
Nguyen AH; Department of Microbiology and Molecular Genetics, University of Texas Health Science Center, Houston, United States of America., Tran TT; Department of Medicine, Division of Infectious Diseases, Houston Methodist Research Institute, Houston, United States of America., Panesso D; Department of Medicine, Division of Infectious Diseases, Houston Methodist Research Institute, Houston, United States of America., Hood KS; Department of Medicine, Division of Infectious Diseases, Houston Methodist Research Institute, Houston, United States of America., Polamraju V; Department of Microbiology and Molecular Genetics, University of Texas Health Science Center, Houston, United States of America., Zhang R; Department of Medicinal Chemistry, University of Washington, Seattle, United States of America., Khan A; Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, United States of America., Miller WR; Department of Medicine, Division of Infectious Diseases, Houston Methodist Research Institute, Houston, United States of America., Mileykovskaya E; Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, United States of America., Shamoo Y; Department of Biosciences, Rice University, Houston, United States of America., Xu L; Department of Medicinal Chemistry, University of Washington, Seattle, United States of America., Vitrac H; Proteomics, Bruker Daltonics, Los Angeles, United States of America., Arias CA; Department of Medicine, Division of Infectious Diseases, Houston Methodist Research Institute, Houston, United States of America. |
| Abstrakt: |
Daptomycin is a last resort lipopeptide antibiotic that disrupts cell membrane (CM) and peptidoglycan homeostasis. Enterococcus faecalis has developed a sophisticated mechanism to avoid daptomycin killing by re-distributing CM anionic phospholipids away from the septum. The CM changes are orchestrated by a three-component regulatory system, designated LiaFSR, with a possible contribution of cardiolipin synthase (Cls). However, the mechanism by which LiaFSR controls the CM response and the role of Cls are unknown. Here, we show that cardiolipin synthase activity is essential for anionic phospholipid redistribution and daptomycin resistance since deletion of the two genes (cls1 and cls2) encoding Cls abolished CM remodeling. We identified LiaY, a transmembrane protein regulated by LiaFSR, and Cls1 as important mediators of CM remodeling required for re-distribution of anionic phospholipid microdomains. Together, our insights provide a mechanistic framework on the enterococcal response to cell envelope antibiotics that could be exploited therapeutically. |
