TY - JOUR
T1 - Antimicrobial sensing coupled with cell membrane remodeling mediates antibiotic resistance and virulence in Enterococcus faecalis
AU - Khan, Ayesha
AU - Davlieva, Milya
AU - Panesso, Diana
AU - Rincon, Sandra
AU - Miller, William R.
AU - Diaz, Lorena
AU - Reyes, Jinnethe
AU - Cruz, Melissa R.
AU - Pemberton, Orville
AU - Nguyen, April H.
AU - Siegel, Sara D.
AU - Planet, Paul J.
AU - Narechania, Apurva
AU - Latorre, Mauricio
AU - Rios, Rafael
AU - Singh, Kavindra
AU - Ton-That, Hung
AU - Garsin, Danielle A.
AU - Tran, Truc T.
AU - Shamoo, Yousif
AU - Arias, Cesar A.
N1 - Funding Information:
ACKNOWLEDGMENTS. This work was supported in part by NIH/National Institutes of Allergy and Infectious Diseases (NIAID) Grants K24-AI121296 (to C.A.A.), R01AI093749 (to C.A.A.), R01AI134637 (to C.A.A.), and R21/R33 AI121519 (to C.A.A.); the University of Texas System Faculty Science and Technology Acquisition and Retention (STAR) Award (to C.A.A.); the University of Texas Health Presidential Award (to C.A.A.); NIAID Grants K08AI135093 (to W.R.M.), K08AI113317 (to T.T.T.), and R01AI080714 (to Y.S.); National Institute of Dental and Cranofacial Research Grants F31DE027295 (to S.D.S.), DE017382 (to H.T.-T.), and DE025015 (to H.T.-T.); the Kopchick Fellowship from the MD Anderson University of Texas Health, Graduate School of Biomedical Sciences (S.D.S.); and NIH/NIAID Grants R01AI076406 (to D.A.G.) and R01AI110432 (to D.A.G.). We thank Drs. Michael C. Lorenz and Heidi Vitrac for input during preparation of this manuscript.
Funding Information:
Competing interest statement: W.R.M. has received grant support from Merck and Entasis Therapeutics, and consulting fees and/or honoraria from Achaogen and Shionogi. C.A.A. has received grant support from Merck, MeMed Diagnostics, and Entasis Therapeutics. All other authors have no competing interests.
Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.
PY - 2019/12/26
Y1 - 2019/12/26
N2 - Bacteria 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 Nterminal 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.
AB - Bacteria 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 Nterminal 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.
KW - Antibiotic resistance
KW - Antimicrobial peptides
KW - Cell membrane adaptation
KW - Daptomycin
KW - Enterococcus faecalis
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U2 - 10.1073/pnas.1916037116
DO - 10.1073/pnas.1916037116
M3 - Article
C2 - 31818937
AN - SCOPUS:85076621634
VL - 116
SP - 26925
EP - 26932
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 52
ER -