Antimicrobial sensing coupled with cell membrane remodeling mediates antibiotic resistance and virulence in Enterococcus faecalis

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dc.citation.firstpage26925
dc.citation.issueNumber52
dc.citation.journalTitlePNAS
dc.citation.lastpage26932
dc.citation.volumeNumber116
dc.contributor.authorKhan, Ayesha
dc.contributor.authorDavlieva, Milya
dc.contributor.authorPanesso, Diana
dc.contributor.authorRincon, Sandra
dc.contributor.authorMiller, William R.
dc.contributor.authorDiaz, Lorena
dc.contributor.authorReyes, Jinnethe
dc.contributor.authorCruz, Melissa R.
dc.contributor.authorPemberton, Orville
dc.contributor.authorNguyen, April H.
dc.contributor.authorSiegel, Sara D.
dc.contributor.authorPlanet, Paul J.
dc.contributor.authorNarechania, Apurva
dc.contributor.authorLatorre, Mauricio
dc.contributor.authorRios, Rafael
dc.contributor.authorSingh, Kavindra V.
dc.contributor.authorTon-That, Hung
dc.contributor.authorGarsin, Danielle A.
dc.contributor.authorTran, Truc T.
dc.contributor.authorShamoo, Yousif
dc.contributor.authorArias, Cesar A.
dc.date.accessioned2020-02-14T16:39:35Z
dc.date.available2020-02-14T16:39:35Z
dc.date.issued2019
dc.description.abstractBacteria have developed several evolutionary strategies to protect their cell membranes (CMs) from the attack of antibiotics and antimicrobial peptides (AMPs) produced by the innate immune system, including remodeling of phospholipid content and localization. Multidrug-resistant Enterococcus faecalis, an opportunistic human pathogen, evolves resistance to the lipopeptide daptomycin and AMPs by diverting the antibiotic away from critical septal targets using CM anionic phospholipid redistribution. The LiaFSR stress response system regulates this CM remodeling via the LiaR response regulator by a previously unknown mechanism. Here, we characterize a LiaR-regulated protein, LiaX, that senses daptomycin or AMPs and triggers protective CM remodeling. LiaX is surface exposed, and in daptomycin-resistant clinical strains, both LiaX and the N-terminal domain alone are released into the extracellular milieu. The N-terminal domain of LiaX binds daptomycin and AMPs (such as human LL-37) and functions as an extracellular sentinel that activates the cell envelope stress response. The C-terminal domain of LiaX plays a role in inhibiting the LiaFSR system, and when this domain is absent, it leads to activation of anionic phospholipid redistribution. Strains that exhibit LiaX-mediated CM remodeling and AMP resistance show enhanced virulence in the Caenorhabditis elegans model, an effect that is abolished in animals lacking an innate immune pathway crucial for producing AMPs. In conclusion, we report a mechanism of antibiotic and AMP resistance that couples bacterial stress sensing to major changes in CM architecture, ultimately also affecting host–pathogen interactions.
dc.identifier.citationKhan, Ayesha, Davlieva, Milya, Panesso, Diana, et al.. "Antimicrobial sensing coupled with cell membrane remodeling mediates antibiotic resistance and virulence in Enterococcus faecalis." <i>PNAS,</i> 116, no. 52 (2019) National Academy of Sciences: 26925-26932. https://doi.org/10.1073/pnas.1916037116.
dc.identifier.digitalAntimicrobial-sensing
dc.identifier.doihttps://doi.org/10.1073/pnas.1916037116
dc.identifier.urihttps://hdl.handle.net/1911/108032
dc.language.isoeng
dc.publisherNational Academy of Sciences
dc.rightsThis open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.titleAntimicrobial sensing coupled with cell membrane remodeling mediates antibiotic resistance and virulence in Enterococcus faecalis
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpublisher version
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