Molecular Basis of Cell Membrane Adaption Against Daptomycin in Enterococcus faecalis

Advisor: Danielle A. Garsin, PhD; Co-Advisor: Cesar A. Arias, MD, PhD)

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 cell membrane 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 cell membrane 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.

Advisory Committee:
Danielle A. Garsin, PhD, Chair
Cesar A. Arias, MD, PhD, Co-Chair
Anna Konovalova, PhD
Dianna Milewicz, MD, PhD
Samuel A. Shelburne, MD, PhD

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Meeting ID: 973 8509 6511