Multicity Outbreak of Linezolid‐Resistant<i>Staphylococcus epidermidis</i>Associated with Clonal Spread of a<i>cfr</i>‐Containing Strain

Bonilla, Hector; Huband, Michael D.; Seidel, Joan; Schmidt, Helen; Lescoe, MaryKay; McCurdy, Sandra P.; Lemmon, M. Megan; Brennan, Lori; Tait-Kamradt, Amelia; Puzniak, Laura; Quinn, John P.

doi:10.1086/656281

Cited by 92 publications

(57 citation statements)

References 30 publications

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“…This mutation has been reported in both staphylococci and enterococci (6,15,34,40,59,61,70,71,87,97,101), and a clear correlation between the number of mutated rRNA operons and the linezolid MIC has been found (2,35,59). Most reports of the G2576U mutation in clinical isolates are associated with some form of increased or prolonged linezolid treatment or with high linezolid usage at the local hospital (29,84), underscoring the importance of judicious use of linezolid in clinical settings.…”

Section: Resistance Caused By 23s Rrna Mutationsmentioning

confidence: 96%

“…This strain is notable because these two rRNA methyltransferase genes are located on the same operon and their coexpression confers resistance to all clinically relevant antibiotics that target the large ribosomal subunit (81). A number of staphylococcal clinical isolates containing cfr in different genetic contexts and parts of the world have subsequently been reported (5,6,16,17,65,67,72,80). In some instances, a connection between the resistant isolates and prior linezolid treatment (6,64) or extensive use of linezolid (72) can be documented.…”

Section: Resistance Caused By Alterations In 23s Rrna Modificationmentioning

confidence: 99%

“…A number of staphylococcal clinical isolates containing cfr in different genetic contexts and parts of the world have subsequently been reported (5,6,16,17,65,67,72,80). In some instances, a connection between the resistant isolates and prior linezolid treatment (6,64) or extensive use of linezolid (72) can be documented. In addition to staphylococci, the cfr gene has also been identified in two Bacillus strains isolated from swine feces (13,102).…”

Section: Resistance Caused By Alterations In 23s Rrna Modificationmentioning

confidence: 99%

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Resistance to Linezolid Caused by Modifications at Its Binding Site on the Ribosome

Long

Vester

2012

Antimicrob Agents Chemother

314

195

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Linezolid is an oxazolidinone antibiotic in clinical use for the treatment of serious infections of resistant Gram-positive bacteria. It inhibits protein synthesis by binding to the peptidyl transferase center on the ribosome. Almost all known resistance mechanisms involve small alterations to the linezolid binding site, so this review will therefore focus on the various changes that can adversely affect drug binding and confer resistance. High-resolution structures of linezolid bound to the 50S ribosomal subunit show that it binds in a deep cleft that is surrounded by 23S rRNA nucleotides. Mutation of 23S rRNA has for some time been established as a linezolid resistance mechanism. Although ribosomal proteins L3 and L4 are located further away from the bound drug, mutations in specific regions of these proteins are increasingly being associated with linezolid resistance. However, very little evidence has been presented to confirm this. Furthermore, recent findings on the Cfr methyltransferase underscore the modification of 23S rRNA as a highly effective and transferable form of linezolid resistance. On a positive note, detailed knowledge of the linezolid binding site has facilitated the design of a new generation of oxazolidinones that show improved properties against the known resistance mechanisms. LINEZOLID

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Section: Resistance Caused By 23s Rrna Mutationsmentioning

confidence: 96%

Section: Resistance Caused By Alterations In 23s Rrna Modificationmentioning

confidence: 99%

Section: Resistance Caused By Alterations In 23s Rrna Modificationmentioning

confidence: 99%

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Resistance to Linezolid Caused by Modifications at Its Binding Site on the Ribosome

Long

Vester

2012

Antimicrob Agents Chemother

314

195

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“…Linezolid resistance is mainly due to mutations in domain V of the 23S rRNA gene, among which G2567U occurs most frequently (Bonilla et al, 2010;Marshall et al, 2002). In addition, the mutations T2500A (Meka et al, 2004), C2534T (LaMarre et al, 2013, G2215A (Kosowska-Shick et al, 2010), T2504A and G2447T (Wong et al, 2010) have been reported among clinical isolates.…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of cfr-positive Staphylococcus aureus isolates from community-onset infectious patients in a county hospital in China

Zhao

Zheng

et al. 2015

Journal of Medical Microbiology

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The cfr gene was detected in 14 meticillin-susceptible Staphylococcus aureus isolates recovered from outpatients with community-onset infections in a county hospital in China. The MIC of linezolid was 4 mg ml 21 in eight isolates and 2 mg ml 21 in six isolates. All isolates were susceptible to vancomycin and teicoplanin, but had elevated MICs for penicillin (0.5-128 mg ml 21), chloramphenicol (2-32 mg ml 21), clindamycin (0.5-128 mg ml 21) and erythromycin (4-128 mg ml 21 ). Nine isolates had mutations on domain V of 23S rRNA and/or the ribosomal L proteins that were not located close to the linezolid-binding pocket. Southern blotting experiments demonstrated that the cfr genes in all 14 isolates resided on plasmids. Sequence analysis of the 5.6 kb cfr-carrying plasmid segment revealed 99 % identity to the corresponding sequences in plasmid pSS-01 from animal staphylococci and plasmid pRM-01 from human staphylococci. Five isolates belonged to sequence type (ST)188 and three to ST965; the two ST types were previously reported in isolates of animal origin in some areas of China. These results indicate that the cfr-carrying plasmids in this study are likely of animal origin. The present study shows that cfr-harbouring S. aureus isolates have emerged in some areas of China and that cfr-carrying isolates may be transmitted between animals and humans.

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“…Mutations in 23S rRNA implicated in linezolid resistance include not only bases near the binding site, like G2061, C2452, A2503, U2504, and G2505, but also bases that are located more distantly from the binding site, such as A2062, G2447, A2453, C2499, U2500, and G2576 (reviewed in reference 8). Additional mechanisms include acquisition of the cfr gene, which encodes a methyltransferase which modifies A2503 in 23S rRNA, and a mutation in the RlmN gene, which naturally modifies A2503 (8)(9)(10)(11)(12)(13)(14). Recently, four nosocomial Staphylococcus epidermidis isolates belonging to the same pulsed-field gel electrophoresis type were described to exhibit partial linezolid dependence, an adaptation reported for only a few antibiotics and bacterial species in the past (15).…”

mentioning

confidence: 99%

Linezolid-Dependent Function and Structure Adaptation of Ribosomes in a Staphylococcus epidermidis Strain Exhibiting Linezolid Dependence

Kokkori¹,

Apostolidi²,

Tsakris³

et al. 2014

Antimicrob Agents Chemother

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b Linezolid-dependent growth was recently reported in Staphylococcus epidermidis clinical strains carrying mutations associated with linezolid resistance. To investigate this unexpected behavior at the molecular level, we isolated active ribosomes from one of the linezolid-dependent strains and we compared them with ribosomes isolated from a wild-type strain. Both strains were grown in the absence and presence of linezolid. Detailed biochemical and structural analyses revealed essential differences in the function and structure of isolated ribosomes which were assembled in the presence of linezolid. The catalytic activity of peptidyltransferase was found to be significantly higher in the ribosomes derived from the linezolid-dependent strain. Interestingly, the same ribosomes exhibited an abnormal ribosomal subunit dissociation profile on a sucrose gradient in the absence of linezolid, but the profile was restored after treatment of the ribosomes with an excess of the antibiotic. Our study suggests that linezolid most likely modified the ribosomal assembly procedure, leading to a new functional ribosomal population active only in the presence of linezolid. Therefore, the higher growth rate of the partially linezolid-dependent strains could be attributed to the functional and structural adaptations of ribosomes to linezolid. O xazolidinone antibiotics inhibit protein synthesis by binding to the peptidyltransferase center (PTC) of the ribosome and inhibiting the growth of bacteria (1). Although it has been suggested that they are involved in the initiation of translation, many reports have been contradictory, mainly because the ratio of drug to ribosome that was used was extremely high (2). Moreover, the inhibitory effect of oxazolidinones on peptide bond formation has not been demonstrated so far, despite structural data suggesting the binding of linezolid in the peptidyltransferase center (3-5). In contrast, linezolid perturbs translational accuracy in vivo, even at concentrations lower than the MIC (6).Linezolid (LZD) was the first FDA-approved oxazolidinone used to treat serious infections due to Gram-positive bacteria. Although LZD was completely synthetic (7), resistance readily emerged and was attributed mainly to mutations in 23S rRNA and ribosomal proteins L3 and L4. Mutations in 23S rRNA implicated in linezolid resistance include not only bases near the binding site, like G2061, C2452, A2503, U2504, and G2505, but also bases that are located more distantly from the binding site, such as A2062, G2447, A2453, C2499, U2500, and G2576 (reviewed in reference 8). Additional mechanisms include acquisition of the cfr gene, which encodes a methyltransferase which modifies A2503 in 23S rRNA, and a mutation in the RlmN gene, which naturally modifies A2503 (8-14). Recently, four nosocomial Staphylococcus epidermidis isolates belonging to the same pulsed-field gel electrophoresis type were described to exhibit partial linezolid dependence, an adaptation reported for only a few antibiotics and bacterial species in the ...

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Multicity Outbreak of Linezolid‐ResistantStaphylococcus epidermidisAssociated with Clonal Spread of acfr‐Containing Strain

Cited by 92 publications

References 30 publications

Resistance to Linezolid Caused by Modifications at Its Binding Site on the Ribosome

Resistance to Linezolid Caused by Modifications at Its Binding Site on the Ribosome

Identification and characterization of cfr-positive Staphylococcus aureus isolates from community-onset infectious patients in a county hospital in China

Linezolid-Dependent Function and Structure Adaptation of Ribosomes in a Staphylococcus epidermidis Strain Exhibiting Linezolid Dependence

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