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

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, as an important mediator of CM remodeling required for re-distribution of anionic phospholipid microdomains via interactions with Cls1. Together, our insights provide a mechanistic framework on the enterococcal response to cell envelope antibiotics that could be exploited therapeutically.

Citation

April H Nguyen, Truc T Tran, Diana Panesso, Kara Hood, Vinathi Polamraju, Rutan Zhang, Ayesha Khan, William R Miller, Eugenia Mileykovskaya, Yousif Shamoo, Libin Xu, Heidi Vitrac, Cesar A Arias. Molecular Basis of Cell Membrane Adaptation in Daptomycin-Resistant Enterococcus faecalis. bioRxiv : the preprint server for biology. 2023 Aug 02

PMID: 37577577

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