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

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dc.citation.firstpage26925en_US
dc.citation.issueNumber52en_US
dc.citation.journalTitlePNASen_US
dc.citation.lastpage26932en_US
dc.citation.volumeNumber116en_US
dc.contributor.authorKhan, Ayeshaen_US
dc.contributor.authorDavlieva, Milyaen_US
dc.contributor.authorPanesso, Dianaen_US
dc.contributor.authorRincon, Sandraen_US
dc.contributor.authorMiller, William R.en_US
dc.contributor.authorDiaz, Lorenaen_US
dc.contributor.authorReyes, Jinnetheen_US
dc.contributor.authorCruz, Melissa R.en_US
dc.contributor.authorPemberton, Orvilleen_US
dc.contributor.authorNguyen, April H.en_US
dc.contributor.authorSiegel, Sara D.en_US
dc.contributor.authorPlanet, Paul J.en_US
dc.contributor.authorNarechania, Apurvaen_US
dc.contributor.authorLatorre, Mauricioen_US
dc.contributor.authorRios, Rafaelen_US
dc.contributor.authorSingh, Kavindra V.en_US
dc.contributor.authorTon-That, Hungen_US
dc.contributor.authorGarsin, Danielle A.en_US
dc.contributor.authorTran, Truc T.en_US
dc.contributor.authorShamoo, Yousifen_US
dc.contributor.authorArias, Cesar A.en_US
dc.date.accessioned2020-02-14T16:39:35Zen_US
dc.date.available2020-02-14T16:39:35Zen_US
dc.date.issued2019en_US
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.en_US
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.en_US
dc.identifier.digitalAntimicrobial-sensingen_US
dc.identifier.doihttps://doi.org/10.1073/pnas.1916037116en_US
dc.identifier.urihttps://hdl.handle.net/1911/108032en_US
dc.language.isoengen_US
dc.publisherNational Academy of Sciencesen_US
dc.rightsThis open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).en_US
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en_US
dc.titleAntimicrobial sensing coupled with cell membrane remodeling mediates antibiotic resistance and virulence in Enterococcus faecalisen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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