Txe, an endoribonuclease of the enterococcal Axe–Txe toxin–antitoxin system, cleaves mRNA and inhibits protein synthesis

Halvorsen, Elizabeth M.; Williams, Julia J.; Bhimani, Azra J.; Billings, Emily A.; Hergenrother, Paul J.

doi:10.1099/mic.0.045492-0

Cited by 42 publications

(39 citation statements)

References 52 publications

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“…Sequencing of the whole plasmid containing Tn1546 revealed that this plasmid contained txe and axe. The genes encoding the AxeTxe system were initially identified on pRUM (a multidrug resistance plasmid) in E. faecium (22,23). The exact role of the AxeTxe system is not fully elucidated, though it has been suggested that it is involved in maintaining plasmid in dividing cells.…”

Section: Discussionmentioning

confidence: 99%

Outbreak of Vancomycin-Susceptible Enterococcus faecium Containing the Wild-Type vanA Gene

Szakacs¹,

Kalan

McConnell³

et al. 2014

J Clin Microbiol

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e Accurate detection of vancomycin-resistant enterococci (VRE) is essential in preventing transmission in health care settings. Chromogenic media are widely used for screening VRE because of fast turnaround times (TAT) and high sensitivity. We report an outbreak of Enterococcus faecium bearing vanA yet susceptible to vancomycin (vancomycin-variable Enterococcus [VVE]). Between October 2009 to March 2011, clinical and screening specimens (n ‫؍‬ 14,747) were screened for VRE using VRE-selective medium and/or PCR. VVE isolates were genotyped to determine relatedness. Plasmids from these isolates were characterized by sequencing. Overall, 52 VVE isolates were identified, comprising 15% of all VRE isolates identified. Isolates demonstrated growth on Brilliance VRE agar (Oxoid) at 24 h of incubation but did not grow on brain heart infusion agar with 6 g/ml vancomycin (Oxoid) or bile esculin azide agar with 6 g/ml vancomycin (Oxoid) and were susceptible to vancomycin. Genotyping of 20 randomly selected VVE isolates revealed that 15/20 were identical, while 5 were highly related. PCR of the VVE transposon confirmed the presence of vanHAXY gene cluster; however, vanS (sensor) and vanR (regulator) genes were absent. The outbreak was controlled through routine infection control measures. We report an emergence of a fit strain of E. faecium containing vanA yet susceptible to vancomycin. Whether this new strain represents VRE has yet to be determined; however, unique testing procedures are required for reliable identification of VVE. Vancomycin-resistant enterococcus (VRE) colonization and infection are increasingly common in both hospital and outpatient settings. Since the initial discovery of VRE during the 1980s in the United Kingdom and France, it has spread to many countries throughout the world (1, 2). In Canada, there has been a small but steady increase in rates of detection of VRE from 0.37 case per 1,000 patient admissions in 1999 to 1.32 in 2005 (3). VRE infection rates increased from 0.02 to 0.05 case per 1,000 admitted patients. Six different types of glycopeptide resistance (vanA, vanB, vanC, vanD, vanE, and vanG) have been described, of which the vanA-and vanB-mediated types are clinically significant in enterococci. Typically, vanA-mediated vancomycin resistance is found in Enterococcus faecium. VRE resistance in vanA-bearing isolates is mediated by the group of genes vanR, vanS, vanH, vanA, and vanX, which are usually carried on the Tn1546 transposon. The expression of these genes leads to replacement of the C-terminal D-Ala residue with D-Lac during cell wall synthesis, thus modifying the vancomycin-binding target. The transposon is often contained on plasmids, making it easy to transfer among enterococcal strains. Historically, there has been little sequence variation in this gene cluster (4).Various studies have shown that infections caused by VRE lead to longer hospital stays, higher mortality, and significantly higher cost than infections caused by vancomycin-susceptible enterococci (5). Therefore, ac...

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Section: Discussionmentioning

confidence: 99%

Outbreak of Vancomycin-Susceptible Enterococcus faecium Containing the Wild-Type vanA Gene

Szakacs¹,

Kalan

McConnell³

et al. 2014

J Clin Microbiol

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“…We sequenced the plasmid associated with one of the VVE strains, K845, isolated from a patient treated with ciprofloxacin, piperacillin-tazobactam, and vancomycin. The plasmid sequence identified a variant of the known enterococcal plasmid pS177, which also shows an IS element (IS1251) inserted in the region between vanRS and vanHAX (15). In this new plasmid, an ϳ8-kb fragment that includes the vanRS regulatory system is deleted.…”

Section: Identification Of Vana-containing Vse and Reversion To Vrementioning

confidence: 99%

Vancomycin-Variable Enterococci Can Give Rise to Constitutive Resistance during Antibiotic Therapy

Thaker

Kalan

Waglechner

et al. 2015

Antimicrob Agents Chemother

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e Vancomycin-resistant enterococci (VRE) are notorious clinical pathogens restricting the use of glycopeptide antibiotics in the clinic setting. Routine surveillance to detect VRE isolated from patients relies on PCR bioassays and chromogenic agar-based test methods. In recent years, we and others have reported the emergence of enterococcal strains harboring a "silent" copy of vancomycin resistance genes that confer a vancomycin-susceptible phenotype (vancomycin-susceptible enterococci [VSE]) and thus escape detection using drug sensitivity screening tests. Alarmingly, these strains are able to convert to a resistance phenotype (VSE¡VRE) during antibiotic treatment, severely compromising the success of therapy. Such strains have been termed vancomycin-variable enterococci (VVE). We have investigated the molecular mechanisms leading to the restoration of resistance in VVE isolates through the whole-genome sequencing of resistant isolates, measurement of resistance gene expression, and quantification of the accumulation of drug-resistant peptidoglycan precursors. The results demonstrate that VVE strains can revert to a VRE phenotype through the constitutive expression of the vancomycin resistance cassette. This is accomplished through a variety of changes in the DNA region upstream of the resistance genes that includes both a deletion of a likely transcription inhibitory secondary structure and the introduction of a new unregulated promoter. The VSE¡VRE transition of VVE can occur in patients during the course of antibiotic therapy, resulting in treatment failure. These VVE strains therefore pose a new challenge to the current regimen of diagnostic tests used for VRE detection in the clinic setting. Fig. 1) (5). VanX is a dipeptidase that removes the D-Ala-D-Ala that continues to be generated by the constitutively expressed chromosomal cell wall biosynthesis machinery. VanH supplies D-Lac by the biochemical reduction of pyruvate, while VanA is an ATP-dependent ligase that synthesizes the ester D-Ala-D-Lac. This depsipeptide is then incorporated into intracellular cell wall precursor biosynthesis, which supplies the reagents required for extracellular peptidoglycan synthesis, which is necessary for cell division and growth.The expression of the vanHAX three-gene cassette is controlled by the two-component regulatory system VanRS, in which VanR is a response regulator and VanS is an integral membrane histidine kinase that recognizes the presence of vancomycin (by direct binding in the case of VanS B [3,6]). The autophosphorylation of VanS and transfer of the phosphate to a VanR aspartyl side chain generates the induction-competent version of VanR that binds to elements upstream of vanH, inducing the expression of vanHAX, which results in resistance (Fig. 1). The vanRS and vanHAX genes have been found on a number of mobile genetic elements, including plasmids and transposons, such as Tn1546. As a result, they have spread globally, and VRE remains an important drug-resistant pathogen in many clinical settings (1). Co...

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“…Two types of pRUM plasmids are currently widespread among VRE and vancomycin-susceptible E. faecium isolates from different hosts. One contains RepA and Axe-Txe from pRUM and, eventually, the mobilization system of pC223 from S. aureus (70,71,(142)(143)(144). The other type is characterized by a RepA protein that is 95% identical to RepA-pRUM, lacking postsegregational killing Axe-Txe and the presence of a MOB P7 relaxase originally detected in pEF1, a plasmid with an environmental origin.…”

Section: Repa_n Enterococcal Plasmidsmentioning

confidence: 99%

“…pRUM-like plasmids (represented by pRUM, p5373c, pS177, and pDO2) are mosaic plasmids of variable size (>30 kb) that comprise diverse genetic elements of different origins (transposons, insertion sequences, small theta-replicating plasmids, bacteriocin clusters). They can be identified as the rep 17 family according to PCR-based typing systems (59) but differ in the RIP sequence, the MOB system, and the presence of the toxin-antitoxin Axe-Txe locus (71,142,143). Both Inc18 and pRUM plasmids are driving the spread of glycopeptide resistance among contemporary isolates of E. faecium by carrying Tn1546 (vanA) or Tn1549 (vanB).…”

Section: Repa_n Enterococcal Plasmidsmentioning

confidence: 99%

The Plasmidome of Firmicutes: Impact on the Emergence and the Spread of Resistance to Antimicrobials

et al. 2015

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The phylum Firmicutes is one of the most abundant groups of prokaryotes in the microbiota of humans and animals and includes genera of outstanding relevance in biomedicine, health care, and industry. Antimicrobial drug resistance is now considered a global health security challenge of the 21st century, and this heterogeneous group of microorganisms represents a significant part of this public health issue.

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Txe, an endoribonuclease of the enterococcal Axe–Txe toxin–antitoxin system, cleaves mRNA and inhibits protein synthesis

Cited by 42 publications

References 52 publications

Outbreak of Vancomycin-Susceptible Enterococcus faecium Containing the Wild-Type vanA Gene

Outbreak of Vancomycin-Susceptible Enterococcus faecium Containing the Wild-Type vanA Gene

Vancomycin-Variable Enterococci Can Give Rise to Constitutive Resistance during Antibiotic Therapy

The Plasmidome of Firmicutes: Impact on the Emergence and the Spread of Resistance to Antimicrobials

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