Molecular basis of cell membrane adaptation in daptomycin-resistant Enterococcus faecalis
April H. Nguyen, Truc T. Tran, Diana Panesso, Kara S. Hood, Vinathi Polamraju, Rutan Zhang, Ayesha Khan, William R. Miller, Eugenia Mileykovskaya, Yousif Shamoo, Libin Xu, Heidi Vitrac, Cesar A. Arias
April H. Nguyen, Truc T. Tran, Diana Panesso, Kara S. Hood, Vinathi Polamraju, Rutan Zhang, Ayesha Khan, William R. Miller, Eugenia Mileykovskaya, Yousif Shamoo, Libin Xu, Heidi Vitrac, Cesar A. Arias
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Research Article Infectious disease

Molecular basis of cell membrane adaptation in daptomycin-resistant Enterococcus faecalis

Abstract

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 redistributing CM anionic phospholipids away from the septum. The CM changes are orchestrated by a 3-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 2 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 redistribution of anionic phospholipid microdomains. Together, our insights provide a mechanistic framework on the enterococcal response to cell envelope antibiotics that could be exploited therapeutically.

Authors

April H. Nguyen, Truc T. Tran, Diana Panesso, Kara S. Hood, Vinathi Polamraju, Rutan Zhang, Ayesha Khan, William R. Miller, Eugenia Mileykovskaya, Yousif Shamoo, Libin Xu, Heidi Vitrac, Cesar A. Arias

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Figure 7

Mechanistic model of cell membrane adaptation in daptomycin-resistant E. faecalis.

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Mechanistic model of cell membrane adaptation in daptomycin-resistant E....
In the absence of daptomycin (top panel), anionic phospholipid microdomains are located at the bacterial division septum where other critical membrane-associated proteins involved in cell division, cell wall or lipid biosynthesis (such as Cls1) are also found. Members of the LiaFSR system (namely liaXYZ) are produced at basal levels and localize in septal areas. LiaX plays an inhibitory role through its C-terminal domain likely via interactions with members of the LiaFSR system. Upon activation of LiaFSR in the presence of daptomycin (bottom panel), the N-terminal domain of LiaX is released to the milieu and interacts with DAP. Concomitant changes in the C-terminus of LiaX cause “activation” of LiaY, generating interactions with Cls1. The LiaY-Cls1 complexes localize in areas away from the septum, presumably in regions where the membrane is being damaged by the antibiotic. Cls1 then produces high amounts of cardiolipin in these nonseptal areas, attracting DAP molecules to these membrane regions, resulting in alteration of the interaction of DAP with its transmembrane target (likely lipid II intermediates), preventing further DAP-mediated damage.