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Article: Molecular Co-occupancy Identifies Transcription Factor Binding Cooperativity In Vivo

Sönmezer, Can / Kleinendorst, Rozemarijn / Imanci, Dilek / Barzaghi, Guido / Villacorta, Laura / Schübeler, Dirk / Benes, Vladimir / Molina, Nacho / Krebs, Arnaud Regis

Molecular cell. 2021 Jan. 21, v. 81, no. 2

2021

Abstract: Gene activation requires the cooperative activity of multiple transcription factors at cis-regulatory elements (CREs). Yet, most transcription factors have short residence time, questioning the requirement of their physical co-occupancy on DNA to achieve ...

Abstract	Gene activation requires the cooperative activity of multiple transcription factors at cis-regulatory elements (CREs). Yet, most transcription factors have short residence time, questioning the requirement of their physical co-occupancy on DNA to achieve cooperativity. Here, we present a DNA footprinting method that detects individual molecular interactions of transcription factors and nucleosomes with DNA in vivo. We apply this strategy to quantify the simultaneous binding of multiple transcription factors on single DNA molecules at mouse CREs. Analysis of the binary occupancy patterns at thousands of motif combinations reveals that high DNA co-occupancy occurs for most types of transcription factors, in the absence of direct physical interaction, at sites of competition with nucleosomes. Perturbation of pairwise interactions demonstrates the function of molecular co-occupancy in binding cooperativity. Our results reveal the interactions regulating CREs at molecular resolution and identify DNA co-occupancy as a widespread cooperativity mechanism used by transcription factors to remodel chromatin.
Keywords	DNA ; DNA footprinting ; gene activation ; mice ; nucleosomes ; regulatory sequences ; transcription factors
Language	English
Dates of publication	2021-0121
Size	p. 255-267.e6.
Publishing place	Elsevier Inc.
Document type	Article
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ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2020.11.015
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Article ; Online: Molecular Co-occupancy Identifies Transcription Factor Binding Cooperativity In Vivo.

Sönmezer, Can / Kleinendorst, Rozemarijn / Imanci, Dilek / Barzaghi, Guido / Villacorta, Laura / Schübeler, Dirk / Benes, Vladimir / Molina, Nacho / Krebs, Arnaud Regis

Molecular cell

2020 Volume 81, Issue 2, Page(s) 255–267.e6

Abstract	Gene activation requires the cooperative activity of multiple transcription factors at cis-regulatory elements (CREs). Yet, most transcription factors have short residence time, questioning the requirement of their physical co-occupancy on DNA to achieve cooperativity. Here, we present a DNA footprinting method that detects individual molecular interactions of transcription factors and nucleosomes with DNA in vivo. We apply this strategy to quantify the simultaneous binding of multiple transcription factors on single DNA molecules at mouse CREs. Analysis of the binary occupancy patterns at thousands of motif combinations reveals that high DNA co-occupancy occurs for most types of transcription factors, in the absence of direct physical interaction, at sites of competition with nucleosomes. Perturbation of pairwise interactions demonstrates the function of molecular co-occupancy in binding cooperativity. Our results reveal the interactions regulating CREs at molecular resolution and identify DNA co-occupancy as a widespread cooperativity mechanism used by transcription factors to remodel chromatin.
MeSH term(s)	Animals ; Binding Sites ; DNA/chemistry ; DNA/genetics ; DNA/metabolism ; DNA Footprinting/methods ; Male ; Mice ; Mouse Embryonic Stem Cells/cytology ; Mouse Embryonic Stem Cells/metabolism ; Nucleosomes/chemistry ; Nucleosomes/metabolism ; Protein Binding ; Regulatory Elements, Transcriptional ; Transcription Factors/chemistry ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Transcription, Genetic
Chemical Substances	Nucleosomes ; Transcription Factors ; DNA (9007-49-2)
Language	English
Publishing date	2020-12-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2020.11.015
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Article: Genome-wide Single-Molecule Footprinting Reveals High RNA Polymerase II Turnover at Paused Promoters

Krebs, Arnaud R / Imanci, Dilek / Hoerner, Leslie / Gaidatzis, Dimos / Burger, Lukas / Schübeler, Dirk

Molecular cell. 2017 Aug. 03, v. 67, no. 3

2017

Abstract: Transcription initiation entails chromatin opening followed by pre-initiation complex formation and RNA polymerase II recruitment. Subsequent polymerase elongation requires additional signals, resulting in increased residence time downstream of the start ...

Abstract	Transcription initiation entails chromatin opening followed by pre-initiation complex formation and RNA polymerase II recruitment. Subsequent polymerase elongation requires additional signals, resulting in increased residence time downstream of the start site, a phenomenon referred to as pausing. Here, we harnessed single-molecule footprinting to quantify distinct steps of initiation in vivo throughout the Drosophila genome. This identifies the impact of promoter structure on initiation dynamics in relation to nucleosomal occupancy. Additionally, perturbation of transcriptional initiation reveals an unexpectedly high turnover of polymerases at paused promoters—an observation confirmed at the level of nascent RNAs. These observations argue that absence of elongation is largely caused by premature termination rather than by stable polymerase stalling. In support of this non-processive model, we observe that induction of the paused heat shock promoter depends on continuous initiation. Our study provides a framework to quantify protein binding at single-molecule resolution and refines concepts of transcriptional pausing.
Keywords	DNA-directed RNA polymerase ; Drosophila ; RNA ; chromatin ; genome ; models ; promoter regions ; transcription initiation
Language	English
Dates of publication	2017-0803
Size	p. 411-422.e4.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2017.06.027
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Article ; Online: Genome-wide Single-Molecule Footprinting Reveals High RNA Polymerase II Turnover at Paused Promoters.

Krebs, Arnaud R / Imanci, Dilek / Hoerner, Leslie / Gaidatzis, Dimos / Burger, Lukas / Schübeler, Dirk

Molecular cell

2017 Volume 67, Issue 3, Page(s) 411–422.e4

Abstract	Transcription initiation entails chromatin opening followed by pre-initiation complex formation and RNA polymerase II recruitment. Subsequent polymerase elongation requires additional signals, resulting in increased residence time downstream of the start site, a phenomenon referred to as pausing. Here, we harnessed single-molecule footprinting to quantify distinct steps of initiation in vivo throughout the Drosophila genome. This identifies the impact of promoter structure on initiation dynamics in relation to nucleosomal occupancy. Additionally, perturbation of transcriptional initiation reveals an unexpectedly high turnover of polymerases at paused promoters-an observation confirmed at the level of nascent RNAs. These observations argue that absence of elongation is largely caused by premature termination rather than by stable polymerase stalling. In support of this non-processive model, we observe that induction of the paused heat shock promoter depends on continuous initiation. Our study provides a framework to quantify protein binding at single-molecule resolution and refines concepts of transcriptional pausing.
MeSH term(s)	Animals ; Binding Sites ; DNA/genetics ; DNA/metabolism ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Drosophila melanogaster/enzymology ; Drosophila melanogaster/genetics ; Genome-Wide Association Study ; HSP70 Heat-Shock Proteins/genetics ; HSP70 Heat-Shock Proteins/metabolism ; Half-Life ; Kinetics ; Promoter Regions, Genetic ; Protein Binding ; Protein Stability ; Proteolysis ; RNA/biosynthesis ; RNA/genetics ; RNA Polymerase II/genetics ; RNA Polymerase II/metabolism ; Single Molecule Imaging ; TATA Box ; Transcription Initiation Site ; Transcription Initiation, Genetic ; Transcription Termination, Genetic ; Transcription, Genetic
Chemical Substances	Drosophila Proteins ; HSP70 Heat-Shock Proteins ; RNA (63231-63-0) ; DNA (9007-49-2) ; RNA Polymerase II (EC 2.7.7.-)
Language	English
Publishing date	2017-08-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2017.06.027
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Article ; Online: A genome-scale map of DNA methylation turnover identifies site-specific dependencies of DNMT and TET activity.

Ginno, Paul Adrian / Gaidatzis, Dimos / Feldmann, Angelika / Hoerner, Leslie / Imanci, Dilek / Burger, Lukas / Zilbermann, Frederic / Peters, Antoine H F M / Edenhofer, Frank / Smallwood, Sébastien A / Krebs, Arnaud R / Schübeler, Dirk

Nature communications

2020 Volume 11, Issue 1, Page(s) 2680

Abstract: DNA methylation is considered a stable epigenetic mark, yet methylation patterns can vary during differentiation and in diseases such as cancer. Local levels of DNA methylation result from opposing enzymatic activities, the rates of which remain largely ... ...

Abstract	DNA methylation is considered a stable epigenetic mark, yet methylation patterns can vary during differentiation and in diseases such as cancer. Local levels of DNA methylation result from opposing enzymatic activities, the rates of which remain largely unknown. Here we developed a theoretical and experimental framework enabling us to infer methylation and demethylation rates at 860,404 CpGs in mouse embryonic stem cells. We find that enzymatic rates can vary as much as two orders of magnitude between CpGs with identical steady-state DNA methylation. Unexpectedly, de novo and maintenance methylation activity is reduced at transcription factor binding sites, while methylation turnover is elevated in transcribed gene bodies. Furthermore, we show that TET activity contributes substantially more than passive demethylation to establishing low methylation levels at distal enhancers. Taken together, our work unveils a genome-scale map of methylation kinetics, revealing highly variable and context-specific activity for the DNA methylation machinery.
MeSH term(s)	Animals ; Binding Sites/genetics ; Cell Line ; Chromosome Mapping ; CpG Islands/genetics ; DNA (Cytosine-5-)-Methyltransferase 1/genetics ; DNA (Cytosine-5-)-Methyltransferase 1/metabolism ; DNA (Cytosine-5-)-Methyltransferases/genetics ; DNA (Cytosine-5-)-Methyltransferases/metabolism ; DNA Demethylation ; DNA Methylation/genetics ; DNA Methyltransferase 3A ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Dioxygenases/genetics ; Dioxygenases/metabolism ; Epigenesis, Genetic/genetics ; Genome/genetics ; Histones/metabolism ; Mice ; Mice, Inbred C57BL ; Mouse Embryonic Stem Cells/metabolism ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/metabolism ; Regulatory Sequences, Nucleic Acid/genetics ; Transcription Factors/metabolism ; Transcription, Genetic/genetics ; DNA Methyltransferase 3B
Chemical Substances	DNA-Binding Proteins ; Histones ; Proto-Oncogene Proteins ; TET1 protein, mouse ; Transcription Factors ; Dioxygenases (EC 1.13.11.-) ; Tet2 protein, mouse (EC 1.13.11.-) ; Tet3 protein, mouse (EC 1.13.11.-) ; DNA (Cytosine-5-)-Methyltransferase 1 (EC 2.1.1.37) ; DNA (Cytosine-5-)-Methyltransferases (EC 2.1.1.37) ; DNA Methyltransferase 3A (EC 2.1.1.37) ; Dnmt1 protein, mouse (EC 2.1.1.37)
Language	English
Publishing date	2020-05-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-020-16354-x
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Article: Draft Genome Sequence of the Serratia rubidaea CIP 103234T Reference Strain, a Human-Opportunistic Pathogen.

Bonnin, Rémy A / Girlich, Delphine / Imanci, Dilek / Dortet, Laurent / Naas, Thierry

Genome announcements

2015 Volume 3, Issue 6

Abstract: We provide here the first genome sequence of a Serratia rubidaea isolate, a human-opportunistic pathogen. This reference sequence will permit a comparison of this species with others of the Serratia genus. ...

Abstract	We provide here the first genome sequence of a Serratia rubidaea isolate, a human-opportunistic pathogen. This reference sequence will permit a comparison of this species with others of the Serratia genus.
Language	English
Publishing date	2015-11-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	2704277-7
ISSN	2169-8287
ISSN	2169-8287
DOI	10.1128/genomeA.01340-15
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Article ; Online: First Occurrence of OXA-72-Producing Acinetobacter baumannii in Serbia.

Dortet, Laurent / Bonnin, Rémy A / Bernabeu, Sandrine / Escaut, Lélia / Vittecoq, Daniel / Girlich, Delphine / Imanci, Dilek / Fortineau, Nicolas / Naas, Thierry

Antimicrobial agents and chemotherapy

2016 Volume 60, Issue 10, Page(s) 5724–5730

Abstract: Here, we characterized the first OXA-72-producing Acinetobacter baumannii isolate (designated MAL) recovered from a urine sample from a Serbian patient. Antimicrobial susceptibility testing, plasmid analysis, and whole-genome sequencing (WGS) were ... ...

Abstract	Here, we characterized the first OXA-72-producing Acinetobacter baumannii isolate (designated MAL) recovered from a urine sample from a Serbian patient. Antimicrobial susceptibility testing, plasmid analysis, and whole-genome sequencing (WGS) were performed to fully characterize the resistome of the A. baumannii MAL clinical isolate. The isolate was multidrug resistant and remained susceptible only to colistin and tigecycline. PCR analysis revealed the presence of the carbapenemase OXA-72, an OXA-40 variant. Extraction by the Kieser method revealed the presence of two plasmids, and one of these, a ca. 10-kb plasmid, harbored the blaOXA-72 gene. WGS revealed 206 contigs corresponding to a genome of 3.9 Mbp in size with a G+C content of 38.8%. The isolate belonged to sequence type 492 and to worldwide clone II (WWCII). Naturally occurring β-lactamase-encoding genes (blaADC-25 and blaOXA-66) were also identified. Aminoglycoside resistance genes encoding one aminoglycoside adenyltransferase (aadA2), three aminoglycoside phosphatases (strA, strB, aphA6), and one 16S RNA methylase (armA) conferring resistance to all aminoglycosides were identified. Resistance to fluoroquinolones was likely due to mutations in gyrA, parC, and parE Of note, the resistome matched perfectly with the antibiotic susceptibility testing results.
MeSH term(s)	Acinetobacter Infections/drug therapy ; Acinetobacter Infections/microbiology ; Acinetobacter baumannii/drug effects ; Acinetobacter baumannii/genetics ; Acinetobacter baumannii/isolation & purification ; Acinetobacter baumannii/metabolism ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Drug Resistance, Multiple, Bacterial/drug effects ; Drug Resistance, Multiple, Bacterial/genetics ; Humans ; Microbial Sensitivity Tests ; Plasmids ; Serbia ; Urinary Tract Infections/drug therapy ; Urinary Tract Infections/microbiology ; beta-Lactamases/genetics ; beta-Lactamases/metabolism
Chemical Substances	Bacterial Proteins ; OXA-72 carbapenemase, Acinetobacter baumannii (EC 3.5.2.6) ; beta-Lactamases (EC 3.5.2.6)
Language	English
Publishing date	2016-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/AAC.01016-16
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Article: Whole-Genome Sequence of a European Clone II and OXA-72-Producing Acinetobacter baumannii Strain from Serbia.

Dortet, Laurent / Bonnin, Rémy A / Girlich, Delphine / Imanci, Dilek / Bernabeu, Sandrine / Fortineau, Nicolas / Naas, Thierry

Genome announcements

2015 Volume 3, Issue 6

Abstract: We report here the draft genome sequence of a carbapenem-resistant Acinetobacter baumannii strain isolated from a patient, a strain which previously stayed in Serbia. This isolate possessed the blaOXA-72 carbapenemase gene. The draft genome sequence ... ...

Abstract	We report here the draft genome sequence of a carbapenem-resistant Acinetobacter baumannii strain isolated from a patient, a strain which previously stayed in Serbia. This isolate possessed the blaOXA-72 carbapenemase gene. The draft genome sequence consists of a total length of 3.91 Mbp, with an average G+C content of 38.8%.
Language	English
Publishing date	2015-12-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	2704277-7
ISSN	2169-8287
ISSN	2169-8287
DOI	10.1128/genomeA.01390-15
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Article ; Online: Fructose 1,6-bisphosphatase deficiency: clinical, biochemical and genetic features in French patients.

Lebigot, Elise / Brassier, Anaïs / Zater, Mokhtar / Imanci, Dilek / Feillet, François / Thérond, Patrice / de Lonlay, Pascale / Boutron, Audrey

Journal of inherited metabolic disease

2015 Volume 38, Issue 5, Page(s) 881–887

Abstract: Fructose-1,6-bisphosphatase (FBPase) deficiency is a very rare autosomal recessive disorder caused by a mutation of the fructose-1,6-bisphosphatase gene(FBP1). Disease is mainly revealed by hypoglycemia and lactic acidosis, both symptoms being ... ...

Abstract	Fructose-1,6-bisphosphatase (FBPase) deficiency is a very rare autosomal recessive disorder caused by a mutation of the fructose-1,6-bisphosphatase gene(FBP1). Disease is mainly revealed by hypoglycemia and lactic acidosis, both symptoms being characteristic for an enzymatic block in the last steps of the gluconeogenesis. Twelve patients with FBPase deficiency were diagnosed in France in the 2001-2013 period, using a diagnostic system based on a single blood sample which allows simultaneous enzyme activity measurement on mononuclear white blood cells and molecular analysis. Sequencing of exons and intron-exon junctions of FBP1 gene was completed in unsolved cases by a gene dosage assay developed for each exon. For most patients, first metabolic decompensation occurred before two years of age with a similar sequence: the triggering factors were fever, fasting, or decrease of food intake. However, diagnosis was made late at a mean age of 3 years, as mitochondrial defects or glycogen storage diseases were firstly suspected. Enzyme activity in leukocytes was dramatically decreased (<10%). Twelve different mutations were identified in 22 alleles among them seven were novels: one missense mutation c.472C > T, one point deletion c.48del, one point duplication c.865dupA, one deletion-insertion, and two splice mutations (c.427-1del and c.825 + 1G > A). We described the first intragenic deletion in FBP1 (g.97,364,754_97,382,011del) in homozygous state. Our report also confirms that this very rare disease is misdiagnosed, as other energetic defects are firstly suspected.
MeSH term(s)	Base Sequence ; Child, Preschool ; Female ; France ; Fructose-1,6-Diphosphatase Deficiency/blood ; Fructose-1,6-Diphosphatase Deficiency/diagnosis ; Fructose-1,6-Diphosphatase Deficiency/genetics ; Fructose-Bisphosphatase/genetics ; Gene Deletion ; Humans ; Infant ; Infant, Newborn ; Inheritance Patterns ; Male ; Molecular Sequence Data ; Mutation, Missense ; RNA Splice Sites/genetics ; Real-Time Polymerase Chain Reaction
Chemical Substances	RNA Splice Sites ; Fructose-Bisphosphatase (EC 3.1.3.11)
Language	English
Publishing date	2015-01-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	438341-2
ISSN	1573-2665 ; 0141-8955
ISSN (online)	1573-2665
ISSN	0141-8955
DOI	10.1007/s10545-014-9804-6
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Article ; Online: Long-lasting successful dissemination of resistance to oxazolidinones in MDR Staphylococcus epidermidis clinical isolates in a tertiary care hospital in France.

Dortet, Laurent / Glaser, Philippe / Kassis-Chikhani, Najiby / Girlich, Delphine / Ichai, Philippe / Boudon, Marc / Samuel, Didier / Creton, Elodie / Imanci, Dilek / Bonnin, Rémy / Fortineau, Nicolas / Naas, Thierry

The Journal of antimicrobial chemotherapy

2017 Volume 73, Issue 1, Page(s) 41–51

Abstract: Objectives: Patient- and procedure-related changes in modern medicine have turned CoNS into one of the major nosocomial pathogens. Treatments of CoNS infections are challenging owing to the large proportion of MDR strains and oxazolidinones often remain ...

Abstract	Objectives: Patient- and procedure-related changes in modern medicine have turned CoNS into one of the major nosocomial pathogens. Treatments of CoNS infections are challenging owing to the large proportion of MDR strains and oxazolidinones often remain the last active antimicrobial molecules. Here, we have investigated a long-lasting outbreak (2010-13) due to methicillin- and linezolid-resistant (LR) CoNS (n = 168), involving 72 carriers and 49 infected patients. Methods: Antimicrobial susceptibilities were tested by the disc diffusion method and MICs were determined by broth microdilution or Etest. The clonal relationship of LR Staphylococcus epidermidis (LRSE) was first determined using a semi-automated repetitive element palindromic PCR (rep-PCR) method. Then, WGS was performed on all cfr-positive LRSE (n = 30) and LRSE isolates representative of each rep-PCR-defined clone (n = 17). Self-transferability of cfr-carrying plasmids was analysed by filter-mating experiments. Results: This outbreak was caused by the dissemination of three clones (ST2, ST5 and ST22) of LRSE. In these clones, linezolid resistance was caused by (i) mutations in the chromosome-located genes encoding the 23S RNA and L3 and L4 ribosomal proteins, but also by (ii) the dissemination of two different self-conjugative plasmids carrying the cfr gene encoding a 23S RNA methylase. By monitoring linezolid prescriptions in two neighbouring hospitals, we highlighted that the spread of LR-CoNS was strongly associated with linezolid use. Conclusions: Physicians should be aware that plasmid-encoded linezolid resistance has started to disseminate among CoNS and that rational use of oxazolidinones is critical to preserve these molecules as efficient treatment options for MDR Gram-positive pathogens.
MeSH term(s)	Anti-Bacterial Agents/therapeutic use ; Disease Outbreaks ; Disk Diffusion Antimicrobial Tests ; Drug Resistance, Multiple, Bacterial/genetics ; Female ; France ; Humans ; Linezolid/therapeutic use ; Male ; Methyltransferases/genetics ; Middle Aged ; RNA, Ribosomal, 23S/genetics ; RNA, Ribosomal, 23S/metabolism ; Staphylococcal Infections/drug therapy ; Staphylococcus epidermidis/drug effects ; Staphylococcus epidermidis/genetics ; Staphylococcus epidermidis/isolation & purification ; Tertiary Care Centers
Chemical Substances	Anti-Bacterial Agents ; RNA, Ribosomal, 23S ; Methyltransferases (EC 2.1.1.-) ; rRNA (adenosine-O-2'-)methyltransferase (EC 2.1.1.230) ; Linezolid (ISQ9I6J12J)
Language	English
Publishing date	2017-12-06
Publishing country	England
Document type	Journal Article
ZDB-ID	191709-2
ISSN	1460-2091 ; 0305-7453
ISSN (online)	1460-2091
ISSN	0305-7453
DOI	10.1093/jac/dkx370
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