A liaR Deletion Restores Susceptibility to Daptomycin and Antimicrobial Peptides in Multidrug-Resistant Enterococcus faecalis
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Daptomycin is a lipopeptide antibiotic that is used clinically against many gram-positive bacterial pathogens and is considered a key frontline bactericidal antibiotic to treat multidrug-resistant enterococci. Emergence of daptomycin resistance during therapy of serious enterococcal infections is a major clinical issue. In this work, we show that deletion of the gene encoding the response regulator, LiaR (a member of the LiaFSR system that controls cell envelope homeostasis), from daptomycin-resistant Enterococcus faecalis not only reversed resistance to 2 clinically available cell membrane-targeting antimicrobials (daptomycin and telavancin), but also resulted in hypersusceptibility to these antibiotics and to a variety of antimicrobial peptides of diverse origin and with different mechanisms of action. The changes in susceptibility to these antibiotics and antimicrobial peptides correlated with in vivo attenuation in a Caenorhabditis elegans model. Mechanistically, deletion of liaR altered the localization of cardiolipin microdomains in the cell membrane. Our findings suggest that LiaR is a master regulator of the enterococcal cell membrane response to diverse antimicrobial agents and peptides; as such, LiaR represents a novel target to restore the activity of clinically useful antimicrobials against these organisms and, potentially, increase susceptibility to endogenous antimicrobial peptides.
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Deletion of LiaR completely reverted DAP susceptibility and restored the organization of CL domains.
“Furthermore, deletion of LiaR completely reverted DAP susceptibility and restored the organization of CL domains (95).”
From Mechanisms of Antibiotic Resistance (2016) · cites this paper as [95]
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- Authors
- Reyes, J., Panesso, D., Tran, T. T., Mishra, N. N., Cruz, M. R., Munita, J. M., Singh, K. V., Yeaman, M. R., Murray, B. E., Shamoo, Y., Garsin, D., Bayer, A. S., & Arias, C. A.
- Affiliations
- Universidad El Bosque (CO)
- University of Houston (US)
- University of California, Los Angeles (US)
- The University of Texas Health Science Center at Houston (US)
- Universidad del Desarrollo (CL)
- Rice University (US)
- Corresponding author
- Reyes, Jinnethe
- ORCID
- Venue
- The Journal of Infectious Diseases
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-10-31
- Volume
- 211
- Issue
- 8
- Pages
- 1317-1325
- ISSN
- 0022-1899 (ISSN-L)
- 1537-6613
- PMC
- PMC4402337
- OpenAlex
- W2100409871
- Cited by
- 94
- References
- 50
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 10 · 2023: 10 · 2022: 5 · 2021: 3 · 2020: 11 · 2019: 6 · 2018: 11 · 2017: 5 · 2016: 17 · 2015: 8
- FWCI
- 6.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Infectious Diseases (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion)
- Funders
- Chinese Academy of Agricultural Sciences
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (R01 AI39108-15, R01AI093749, R01AI076406, R01AI080714, K08AI113317, R01AI039108, R01AI047923)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK056338)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
- Life Sciences › Immunology and Microbiology › Microbiology › Antimicrobial Peptides and Activities
- Keywords
- liars, Enterococcus faecalis, daptomycin resistance, multidrug resistance, antimicrobial peptides, telavancin, plasma membrane, cell envelope homeostasis, response regulator, Caenorhabditis elegans model, antibiotic susceptibility restoration
- MeSH terms
- Animals, Anti-Infective Agents, Anti-Bacterial Agents, Bacterial Proteins, Cardiolipins, Cell Membrane, Microbial Sensitivity Tests, Peptides, Enterococcus faecalis, Gram-Positive Bacterial Infections, Caenorhabditis elegans, Sequence Deletion, Daptomycin, Drug Resistance, Multiple, Bacterial
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