Cited by 377Antibiotic Resistance in BacteriaBacterial Genetics and BiotechnologyAntimicrobial Resistance in Staphylococcus

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Genetic Basis for In Vivo Daptomycin Resistance in Enterococci

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Arias, Cesar A., Panesso, Diana, McGrath, Danielle M., Qin, Xiang, Mojica, Maria F., Miller, Corwin, Diaz, Lorena, Tran, Truc T., Rincon, Sandra, Barbu, E. Magda, Reyes, Jinnethe, Roh, Jung H., Lobos, Elizabeth, Sodergren, Erica, Pasqualini, Renata, Arap, Wadih, Quinn, John P., Shamoo, Yousif, Murray, Barbara E., Weinstock, George M.·2011·New England Journal of Medicine

DOI 10.1056/nejmoa1011138PMC PMC3205971

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Abstract

BACKGROUND: Daptomycin is a lipopeptide with bactericidal activity that acts on the cell membrane of enterococci and is often used off-label to treat patients infected with vancomycin-resistant enterococci. However, the emergence of resistance to daptomycin during therapy threatens its usefulness. METHODS: We performed whole-genome sequencing and characterization of the cell envelope of a clinical pair of vancomycin-resistant Enterococcus faecalis isolates from the blood of a patient with fatal bacteremia; one isolate (S613) was from blood drawn before treatment and the other isolate (R712) was from blood drawn after treatment with daptomycin. The minimal inhibitory concentrations (MICs) of these two isolates were 1 and 12 μg per milliliter, respectively. Gene replacements were made to exchange the alleles found in isolate S613 with those in isolate R712. RESULTS: Isolate R712 had in-frame deletions in three genes. Two genes encoded putative enzymes involved in phospholipid metabolism, GdpD (which denotes glycerophosphoryl diester phosphodiesterase) and Cls (which denotes cardiolipin synthetase), and one gene encoded a putative membrane protein, LiaF (which denotes lipid II cycle-interfering antibiotics protein but whose exact function is not known). LiaF is predicted to be a member of a three-component regulatory system (LiaFSR) involved in the stress-sensing response of the cell envelope to antibiotics. Replacement of the liaF allele of isolate S613 with the liaF allele from isolate R712 quadrupled the MIC of daptomycin, whereas replacement of the gdpD allele had no effect on MIC. Replacement of both the liaF and gdpD alleles of isolate S613 with the liaF and gdpD alleles of isolate R712 raised the daptomycin MIC for isolate S613 to 12 μg per milliliter. As compared with isolate S613, isolate R712--the daptomycin-resistant isolate--had changes in the structure of the cell envelope and alterations in membrane permeability and membrane potential. CONCLUSIONS: Mutations in genes encoding LiaF and a GdpD-family protein were necessary and sufficient for the development of resistance to daptomycin during the treatment of vancomycin-resistant enterococci. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health.).

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Self-citation

Authors: Arias, C. A., Panesso, D., McGrath, D. M., Qin, X., Mojica, M. F., Miller, C., Diaz, L., Tran, T. T., Rincon, S., Barbu, E. M., Reyes, J., Roh, J. H., Lobos, E., Sodergren, E., Pasqualini, R., Arap, W., Quinn, J. P., Shamoo, Y., Murray, B. E., & Weinstock, G. M.
Affiliations: Universidad El Bosque (CO)
The University of Texas MD Anderson Cancer Center (US)
Baylor College of Medicine (US)
Rice University (US)
University of Houston (US)
Washington University in St. Louis (US)
Pfizer (United States) (US)
ORCID: Panesso, Diana
McGrath, Danielle M.
Qin, Xiang
Tran, Truc T.
Barbu, E. Magda
Reyes, Jinnethe
Sodergren, Erica
Pasqualini, Renata
Arap, Wadih
Quinn, John P.
Shamoo, Yousif
Murray, Barbara E.
Weinstock, George M.
Venue: New England Journal of Medicine
Publisher: Massachusetts Medical Society
Published: 2011-09-08
Volume: 365
Issue: 10
Pages: 892-900
ISSN: 0028-4793 (ISSN-L)
1533-4406
DOI: 10.1056/nejmoa1011138
PMC: PMC3205971
OpenAlex: W2129864306
Cited by: 377
References: 37
Citations by year: 2026: 17 · 2025: 20 · 2024: 20 · 2023: 22 · 2022: 20 · 2021: 18 · 2020: 35 · 2019: 18 · 2018: 20 · 2017: 21 · 2016: 32 · 2015: 33 · 2014: 35 · 2013: 28 · 2012: 32
FWCI: 14.50
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: New England Journal of Medicine (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
Rutgers University Community Repository (Rutgers University) (submittedVersion)
LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion)
Funders: National Human Genome Research Institute (U54HG004968)
National Institute of Allergy and Infectious Diseases (R37AI047923, R01AI093749, R00AI072961, R01AI080714, R01AI067861)
Topics: Health Sciences › Medicine › Microbiology (medical) › Antibiotic Resistance in Bacteria
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
Health Sciences › Medicine › Infectious Diseases › Antimicrobial Resistance in Staphylococcus
Keywords: daptomycin resistance, vancomycin-resistant enterococci, Enterococcus faecalis, envelope stress response, membrane permeability, membrane potential, bacteremia, gene replacement, minimum inhibitory concentration, phospholipid metabolism
MeSH terms: Anti-Bacterial Agents, Genes, Bacterial, Humans, Microbial Sensitivity Tests, Mutation, Enterococcus faecalis, Bacteremia, Genome, Bacterial, Gram-Positive Bacterial Infections, Sequence Analysis, DNA, Daptomycin, Vancomycin Resistance, Drug Resistance, Bacterial, Microscopy, Electron, Transmission

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Genetic Basis for In Vivo Daptomycin Resistance in Enterococci

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