Dataset Information

CTX-M Enzymes: Origin and Diffusion.

ABSTRACT: CTX-M ?-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, ?-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 ?-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.

SUBMITTER: Canton R

PROVIDER: S-EPMC3316993 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Publications

CTX-M Enzymes: Origin and Diffusion.

Cantón Rafael R González-Alba José María JM Galán Juan Carlos JC

Frontiers in microbiology 20120402

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 suc ...[more]

PMID: 22485109

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Project description:Extended-spectrum beta-lactamases (ESBL) constitute a key antibiotic-resistance mechanism affecting Gram-negative bacteria, and also an excellent model for studying evolution in real time. A shift in the epidemiology of ESBLs is being observed, which is characterized by the explosive diversification and increase in frequency of the CTX-M-type beta-lactamases in different settings. This provides a unique opportunity for studying a protein evolutionary radiation by the sequential acquisition of specific mutations enhancing protein efficiency and fitness concomitantly. The existence of driver antibiotic molecules favoring protein divergence has been investigated by combining evolutionary analyses and experimental site-specific mutagenesis. Phylogenetic reconstruction with all the CTX-M variants described so far provided a hypothetical evolutionary scenario showing at least three diversification events. CTX-M-3 was likely the enzyme at the origin of the diversification in the CTX-M-1 cluster, which was coincident with positive selection acting on several amino acid positions. Sixty-three CTX-M-3 derivatives containing all combinations of mutations under positively selected positions were constructed, and their phenotypic efficiency was evaluated. The CTX-M-3 diversification process can only be explained in a complex selective landscape with at least two antibiotics (cefotaxime and ceftazidime), indicating the need to invoke mixtures of selective drivers in order to understand the final evolutionary outcome. Under this hypothesis, we found congruent results between the in silico and in vitro analyses of evolutionary trajectories. Three pathways driving the diversification of CTX-M-3 towards the most complex and efficient variants were identified. Whereas the P167S pathway has limited possibilities of further diversification, the D240G route shows a robust diversification network. In the third route, drift may have played a role in the early stages of CTX-M-3 evolution. Antimicrobial agents should not be considered only as selectors for efficient mechanisms of resistance but also as diversifying agents of the evolutionary trajectories. Different trajectories were identified using a combination of phylogenetic reconstructions and directed mutagenesis analyses, indicating that such an approach might be useful to fulfill the desirable goal of predicting evolutionary trajectories in antimicrobial resistance.

Project description:Twelve evolutionarily unrelated oxidoreductases form enzyme complexes that catalyze the simultaneous coupling of exergonic and endergonic oxidation-reduction reactions to circumvent thermodynamic barriers and minimize free energy loss in a process known as flavin-based electron bifurcation. Common to these 12 bifurcating (Bf) enzymes are protein-bound flavin, the proposed site of bifurcation, and the electron carrier ferredoxin. Despite the documented role of Bf enzymes in balancing the redox state of intracellular electron carriers and in improving the efficiency of cellular metabolism, a comprehensive description of the diversity and evolutionary history of Bf enzymes is lacking. Here, we report the taxonomic distribution, functional diversity, and evolutionary history of Bf enzyme homologs in 4,588 archaeal, bacterial, and eukaryal genomes and 3,136 community metagenomes. Bf homologs were primarily detected in the genomes of anaerobes, including those of sulfate-reducers, acetogens, fermenters, and methanogens. Phylogenetic analyses of Bf enzyme catalytic subunits (oxidoreductases) suggest they were not a property of the Last Universal Common Ancestor of Archaea and Bacteria, which is consistent with the limited and unique taxonomic distributions of enzyme homologs among genomes. Further, phylogenetic analyses of oxidoreductase subunits reveal that non-Bf homologs predate Bf homologs. These observations indicate that multiple independent recruitments of flavoproteins to existing oxidoreductases enabled coupling of numerous new electron Bf reactions. Consistent with the role of these enzymes in the energy metabolism of anaerobes, homologs of Bf enzymes were enriched in metagenomes from subsurface environments relative to those from surface environments. Phylogenetic analyses of homologs from metagenomes reveal that the earliest evolving homologs of most Bf enzymes are from subsurface environments, including fluids from subsurface rock fractures and hydrothermal systems. Collectively, these data suggest strong selective pressures drove the emergence of Bf enzyme complexes via recruitment of flavoproteins that allowed for an increase in the efficiency of cellular metabolism and improvement in energy capture in anaerobes inhabiting a variety of subsurface anoxic habitats where the energy yield of oxidation-reduction reactions is generally low.

Dataset Information

CTX-M Enzymes: Origin and Diffusion.

Publications

CTX-M Enzymes: Origin and Diffusion.

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