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CTX-M Enzymes: Origin and Diffusion.

Cantón R, González-Alba JM, Galán JC - Front Microbiol (2012)

Bottom Line: Nevertheless, more variants of CTX-M enzymes, including those not inhibited by β-lactamase inhibitors such as clavulanic acid (IR-CTX-M variants), only obtained under in in vitro experiments, are still waiting to emerge in the clinical setting.Penetration and the later global spread of CTX-M producing organisms have been produced with the participation of the so-called "epidemic resistance plasmids" often carried in multi-drug resistant and virulent high-risk clones.All these facts but also the incorporation and co-selection of emerging resistance determinants within CTX-M producing bacteria, such as those encoding carbapenemases, depict the currently complex pandemic scenario of multi-drug resistant isolates.

View Article: PubMed Central - PubMed

Affiliation: Servicio de Microbiología, Hospital Universitario Ramón y Cajal, CIBER en Epidemiología y Salud Pública and Instituto Ramón y Cajal de Investigación Sanitaria Madrid, Spain.

ABSTRACT
CTX-M β-lactamases are considered a paradigm in the evolution of a resistance mechanism. Incorporation of different chromosomal bla(CTX-M) related genes from different species of Kluyvera has derived in different CTX-M clusters. In silico analyses have shown that this event has occurred at least nine times; in CTX-M-1 cluster (3), CTX-M-2 and CTX-M-9 clusters (2 each), and CTX-M-8 and CTX-M-25 clusters (1 each). This has been mainly produced by the participation of genetic mobilization units such as insertion sequences (ISEcp1 or ISCR1) and the later incorporation in hierarchical structures associated with multifaceted genetic structures including complex class 1 integrons and transposons. The capture of these bla(CTX-M) genes from the environment by highly mobilizable structures could have been a random event. Moreover, after incorporation within these structures, β-lactam selective force such as that exerted by cefotaxime and ceftazidime has fueled mutational events underscoring diversification of different clusters. Nevertheless, more variants of CTX-M enzymes, including those not inhibited by β-lactamase inhibitors such as clavulanic acid (IR-CTX-M variants), only obtained under in in vitro experiments, are still waiting to emerge in the clinical setting. Penetration and the later global spread of CTX-M producing organisms have been produced with the participation of the so-called "epidemic resistance plasmids" often carried in multi-drug resistant and virulent high-risk clones. All these facts but also the incorporation and co-selection of emerging resistance determinants within CTX-M producing bacteria, such as those encoding carbapenemases, depict the currently complex pandemic scenario of multi-drug resistant isolates.

No MeSH data available.


Alignment of upstream sequences in different blaCTX-M gene clusters. Different blaCTX-M genes belonging to the same cluster share an identical DNA sequence in upstream region, suggesting the same origin (A). Nevertheless, the loss of alignment among different upstream sequences from different blaCTX-M genes belonging to different clusters (included in the box squared) but theoretically derived from the same ancestral source in Kluyvera georgiana suggesting that these clusters had different sources (B).
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Figure 5: Alignment of upstream sequences in different blaCTX-M gene clusters. Different blaCTX-M genes belonging to the same cluster share an identical DNA sequence in upstream region, suggesting the same origin (A). Nevertheless, the loss of alignment among different upstream sequences from different blaCTX-M genes belonging to different clusters (included in the box squared) but theoretically derived from the same ancestral source in Kluyvera georgiana suggesting that these clusters had different sources (B).

Mentions: On the other hand, spacer sequences between ISEcp1 and blaCTX-M genes have been well studied. The genetic distance between IS and blaCTX-M gene is related to cephalosporin MIC values (Ma et al., 2011). These distances ranged between 48 and 127 bp in blaCTX-M-1 gene cluster, between 34 and 42 bp in blaCTX-M-9 gene cluster (but more than 300 bp if ISCR1 is upstream of blaCTX-M) and around 40–52 in blaCTX-M-25 and blaCTX-M-8 gene clusters respectively. When the homology among spacer sequences of blaCTX-M-1 gene cluster was analyzed, all but blaCTX-M-10 and blaCTX-M-53 maintained a common region (known as V and W sequences). This suggests that these blaCTX-M genes belonging to CTX-M-1 cluster could derive from a single transposition event. A similar conclusion can be obtained when considering ISEcp1 and blaCTX-M genes belonging to blaCTX-M-9 (Y sequence), blaCTX-M-8 and blaCTX-M-25 (Figure 5). In all these clusters, the ancestral source was K. georgiana. However the lack of homology among spacer sequences of these blaCTX-M gene clusters suggests a different source in each case. These results reveal that non-described Kluyvera species (or another organism source) could be the origin of clusters ascribed to K. georgiana (see Figure 3 about the phylogenetic tree of 16S rDNA of Kluyvera spp. where more species of Kluyvera can be suggested according to bootstrap values).


CTX-M Enzymes: Origin and Diffusion.

Cantón R, González-Alba JM, Galán JC - Front Microbiol (2012)

Alignment of upstream sequences in different blaCTX-M gene clusters. Different blaCTX-M genes belonging to the same cluster share an identical DNA sequence in upstream region, suggesting the same origin (A). Nevertheless, the loss of alignment among different upstream sequences from different blaCTX-M genes belonging to different clusters (included in the box squared) but theoretically derived from the same ancestral source in Kluyvera georgiana suggesting that these clusters had different sources (B).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3316993&req=5

Figure 5: Alignment of upstream sequences in different blaCTX-M gene clusters. Different blaCTX-M genes belonging to the same cluster share an identical DNA sequence in upstream region, suggesting the same origin (A). Nevertheless, the loss of alignment among different upstream sequences from different blaCTX-M genes belonging to different clusters (included in the box squared) but theoretically derived from the same ancestral source in Kluyvera georgiana suggesting that these clusters had different sources (B).
Mentions: On the other hand, spacer sequences between ISEcp1 and blaCTX-M genes have been well studied. The genetic distance between IS and blaCTX-M gene is related to cephalosporin MIC values (Ma et al., 2011). These distances ranged between 48 and 127 bp in blaCTX-M-1 gene cluster, between 34 and 42 bp in blaCTX-M-9 gene cluster (but more than 300 bp if ISCR1 is upstream of blaCTX-M) and around 40–52 in blaCTX-M-25 and blaCTX-M-8 gene clusters respectively. When the homology among spacer sequences of blaCTX-M-1 gene cluster was analyzed, all but blaCTX-M-10 and blaCTX-M-53 maintained a common region (known as V and W sequences). This suggests that these blaCTX-M genes belonging to CTX-M-1 cluster could derive from a single transposition event. A similar conclusion can be obtained when considering ISEcp1 and blaCTX-M genes belonging to blaCTX-M-9 (Y sequence), blaCTX-M-8 and blaCTX-M-25 (Figure 5). In all these clusters, the ancestral source was K. georgiana. However the lack of homology among spacer sequences of these blaCTX-M gene clusters suggests a different source in each case. These results reveal that non-described Kluyvera species (or another organism source) could be the origin of clusters ascribed to K. georgiana (see Figure 3 about the phylogenetic tree of 16S rDNA of Kluyvera spp. where more species of Kluyvera can be suggested according to bootstrap values).

Bottom Line: Nevertheless, more variants of CTX-M enzymes, including those not inhibited by β-lactamase inhibitors such as clavulanic acid (IR-CTX-M variants), only obtained under in in vitro experiments, are still waiting to emerge in the clinical setting.Penetration and the later global spread of CTX-M producing organisms have been produced with the participation of the so-called "epidemic resistance plasmids" often carried in multi-drug resistant and virulent high-risk clones.All these facts but also the incorporation and co-selection of emerging resistance determinants within CTX-M producing bacteria, such as those encoding carbapenemases, depict the currently complex pandemic scenario of multi-drug resistant isolates.

View Article: PubMed Central - PubMed

Affiliation: Servicio de Microbiología, Hospital Universitario Ramón y Cajal, CIBER en Epidemiología y Salud Pública and Instituto Ramón y Cajal de Investigación Sanitaria Madrid, Spain.

ABSTRACT
CTX-M β-lactamases are considered a paradigm in the evolution of a resistance mechanism. Incorporation of different chromosomal bla(CTX-M) related genes from different species of Kluyvera has derived in different CTX-M clusters. In silico analyses have shown that this event has occurred at least nine times; in CTX-M-1 cluster (3), CTX-M-2 and CTX-M-9 clusters (2 each), and CTX-M-8 and CTX-M-25 clusters (1 each). This has been mainly produced by the participation of genetic mobilization units such as insertion sequences (ISEcp1 or ISCR1) and the later incorporation in hierarchical structures associated with multifaceted genetic structures including complex class 1 integrons and transposons. The capture of these bla(CTX-M) genes from the environment by highly mobilizable structures could have been a random event. Moreover, after incorporation within these structures, β-lactam selective force such as that exerted by cefotaxime and ceftazidime has fueled mutational events underscoring diversification of different clusters. Nevertheless, more variants of CTX-M enzymes, including those not inhibited by β-lactamase inhibitors such as clavulanic acid (IR-CTX-M variants), only obtained under in in vitro experiments, are still waiting to emerge in the clinical setting. Penetration and the later global spread of CTX-M producing organisms have been produced with the participation of the so-called "epidemic resistance plasmids" often carried in multi-drug resistant and virulent high-risk clones. All these facts but also the incorporation and co-selection of emerging resistance determinants within CTX-M producing bacteria, such as those encoding carbapenemases, depict the currently complex pandemic scenario of multi-drug resistant isolates.

No MeSH data available.