The multidrug-resistant human pathogen Clostridium difficile has a highly mobile, mosaic genome

Sebaihia, Mohammed; Wren, Brendan W.; Mullany, Peter; Fairweather, Neil F.; Minton, Nigel P.; Stabler, Richard A.; Thomson, Nicholas R.; Roberts, Adam P.; Cerdeño-Tárraga, Ana; Wang, Hongmei; Holden, Matthew T. G.; Wright, Anne; Churcher, Carol; Quail, Michael A.; Baker, Stephen; Bason, Nathalie; Brooks, Karen; Chillingworth, Tracey; Cronin, Ann; Davis, Paul A.; Dowd, Linda; Fraser, Audrey; Feltwell, Theresa; Hance, Zahra; Holroyd, S.; Jagels, Kay; Moule, Sharon; Mungall, Karen; Price, Claire; Rabbinowitsch, Ester; Sharp, Sarah; Simmonds, Mark; Stevens, Kim; Unwin, Louise; Whithead, Sally; Dupuy, Bruno; Dougan, Gordon; Barrell, Bart; Parkhill, Julian

doi:10.1038/ng1830

Cited by 819 publications

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“…In the first C. difficile genome to be sequenced, str. 630 (RT 012), mobile elements accounted for ~10% of the genome and included a plasmid, prophages, transposons, IStrons, genomic islands, CRISPRs and a skin element (Sebaihia et al, 2006). This has remained consistent in the annotated genomes of other strains published since, including M120 (clade 5), and R20291 (clade 2) (He et al, 2010;Stabler et al, 2009).…”

Section: Accepted Manuscriptmentioning

confidence: 71%

“…630 contained seven conjugative transposons (CTn1-CTn7), and one mobilisable transposon Tn5398 (Sebaihia et al, 2006). The conjugative transposons are divided into two main families based on their conjugation modules, the Tn916 family, and the Tn1549 family (Sebaihia et al, 2006).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…The very limited number of plasmids that have been sequenced, such as the plasmid from str. 630, pCD630, have all been cryptic in function (Sebaihia et al, 2006). Genes mediating virulence…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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Clostridium difficile infection: Evolution, phylogeny and molecular epidemiology

Elliott

Androga

Knight

et al. 2017

Infection, Genetics and Evolution

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Over the recent decades, Clostridium difficile infection (CDI) has emerged as a global public health threat. Despite growing attention, C. difficile remains a poorly understood pathogen, however, the exquisite sensitivity offered by next generation sequencing (NGS) technology has enabled analysis of the genome of C. difficile, giving us access to massive genomic data on factors such as virulence, evolution, and genetic relatedness within C. difficile groups. NGS has also demonstrated excellence in investigations of outbreaks and disease transmission, in both small and large-scale applications. This review summarizes the molecular epidemiology, evolution, and phylogeny of C. difficile, one of the most important pathogens worldwide in the current antibiotic resistance era.

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Section: Accepted Manuscriptmentioning

confidence: 71%

Section: Accepted Manuscriptmentioning

confidence: 99%

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Clostridium difficile infection: Evolution, phylogeny and molecular epidemiology

Elliott

Androga

Knight

et al. 2017

Infection, Genetics and Evolution

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“…Gene transfer was suggested to be mediated by megaplasmids, based on the identification of 10 such plasmids carrying CRISPR arrays 22,33 . Interestingly, a CRISPR array was also found within a Clostridium difficile prophage, and it was suggested that the phage uses the CRISPR to limit dispersal of competing phages 34 .…”

Section: Evolution Of Crispr Systemsmentioning

confidence: 99%

CRISPR — a widespread system that provides acquired resistance against phages in bacteria and archaea

2008

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Arrays of clustered, regularly spaced short palindromic repeats (CRISPR) are widespread in the genomes of many bacteria and almost all archaea. These arrays are composed of direct repeats sized 24-47 bp separated by similarly sized non-repetitive sequences (spacers). It was recently experimentally shown that CRISPR arrays, along with a group of associated proteins, confer resistance to phage. Following exposure to phage, bacteria integrate new spacer sequences that are derived from the phage genome. Acquisition of these spacers enables the bacterial cell to shutdown the phage attack, presumably by an RNA-interference-like mechanism. This Progress discusses the structure and function of CRISPRs and the implications of this new antiviral mechanism in bacteria.2 Bacteriophages constitute the most populous life-forms on Earth 1 . In sea water, an environment in which phage abundance has been extensively studied, it has been estimated that there are 5-10 phage for every bacterial cell 2 . Despite being outnumbered by phage, bacteria proliferate and avoid extinction by using a battery of innate phageresistance mechanisms such as restriction enzymes and abortive infection 3 . In this Progress article we describe the CRISPR system, a recently discovered defence mechanism, which is remarkable because it confers acquired phage resistance in Bacteria and Archaea. A hallmark of this system are arrays of short direct repeats interspersed by non-repetitive spacer sequences, the so-called Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR). Additional components of the system include CRISPRassociated (CAS) genes and a leader sequence (Fig. 1A). Brief history of CRISPR researchThe first report that described a CRISPR array, in 1987, was from Ishino et al. who found 14 repeats of 29bp interspersed by 32-33bp non-repeating spacer sequences 4,5 , adjacent to the isozyme converting alkaline phosphatase (iap) gene in Escherichia coli. In subsequent years similar CRISPR arrays were found in Mycobacterium tuberculosis 6 , Haloferax mediterranei 7 , Methanocaldococcus jannaschii 8 , Thermotoga maritima 9 and other bacteria and archaea. The accumulation of sequenced microbial genomes allowed genome-wide computational searches for CRISPRs (the first such analysis was carried out by Mojica et al. in 2000 10 ), and the most recent computational analyses revealed that CRISPRs are found in ~40% of bacterial and ~90% of archaeal genomes sequenced to date 11, 12 (Box 1).In parallel to the initial appreciation of the abundance of CRISPRs 13 , Jansen et al. identified four CRISPR-associated (CAS) genes that were almost always found adjacent to the repeat arrays 14 . Subsequent studies initiated by Koonin and colleagues 15, 16 and Haft et al. 17 uncovered 25-45 additional CAS genes appearing in close proximity to the arrays. The same set of genes is absent from genomes that lack CRISPRs.Several hypotheses for the function of CRISPRs have been proposed. Early in 1995 Mojica et al. suggested that the repeats were involved i...

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“…Conversely, in tetracycline-resistant, erm(TR)-positive S. pyogenes isolates, a completely different genetic element, in which erm(TR) is linked to the tet(O) gene, has recently been characterized (3). This new structure, designated ICESp2905 (ϳ66 kb), results from two separate fragments, one containing erm(TR) and one containing tet(O), being integrated into a scaffold of clostridial origin (a putative ICE from Clostridium difficile strain 630 [16]). Remarkably, both ICESp1108 and ICESp2905 are integrated in the chromosome at the 3= end of the conserved RNA uracil methyltransferase (rum) gene, which is an integration hot spot for several mobile streptococcal elements (3).…”

mentioning

confidence: 99%

ICE Sp2905 , the erm (TR)- tet (O) Element of Streptococcus pyogenes, Is Formed by Two Independent Integrative and Conjugative Elements

Giovanetti

Brenciani

Tiberi

et al. 2012

Antimicrob Agents Chemother

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In ICESp2905, a widespread erm(TR)-and tet(O)-carrying genetic element of Streptococcus pyogenes, the two resistance determinants are contained in separate fragments inserted into a scaffold of clostridial origin. ICESp2905 (ϳ65.6 kb) was transferable not only in its regular form but also in a defective form lacking the erm(TR) fragment (ICESp2906, ϳ53.0 kb). The erm(TR) fragment was also an independent integrative and conjugative element (ICE) (ICESp2907, ϳ12.6 kb). ICESp2905 thus results from one ICE (ICESp2907) being integrated into another (ICESp2906).

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The multidrug-resistant human pathogen Clostridium difficile has a highly mobile, mosaic genome

Cited by 819 publications

References 50 publications

Clostridium difficile infection: Evolution, phylogeny and molecular epidemiology

Clostridium difficile infection: Evolution, phylogeny and molecular epidemiology

CRISPR — a widespread system that provides acquired resistance against phages in bacteria and archaea

ICE Sp2905 , the erm (TR)- tet (O) Element of Streptococcus pyogenes, Is Formed by Two Independent Integrative and Conjugative Elements

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