Molecular Basis of Cell Membrane Adaption Against Daptomycin in Enterococcus faecalis

<p>Daptomycin is a last-resort lipopeptide antibiotic that disrupts cell membrane (CM) and peptidoglycan homeostasis (Grein et al., 2020a; Müller et al., 2016a). Enterococcus faecalis has developed a sophisticated mechanism to avoid daptomycin killing by redistributing 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) (Cesar A Arias et al., 2011a; Khan et al., 2019b; Palmer et al., 2011a; Panesso et al., 2015a; Reyes et al., 2015a). 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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2024

Authors dc:creator

• Nguyen, April
• <p>0000-0003-3814-6884</p>

Contributors dc:contributor

• Cesar Arias
• Danielle Garsin
• Anna Konovalova

• enterococci
• daptomycin
• Medical Microbiology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1371

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2427