Mini reviewCTX-M-type β-lactamases: A successful story of antibiotic resistance
Introduction
The introduction of expanded-spectrum cephalosporins in clinical practice, in the early 1980s, represented a major breakthrough for the treatment of infections caused by Enterobacteriaceae and other Gram-negative pathogens. At the same time, the massive use of expanded-spectrum cephalosporins generated a selective pressure that was followed by the rapid emergence of new β-lactamases that were able to degrade and confer resistance to these compounds, named extended-spectrum β-lactamases (ESBLs).
Two major strategies of ESBL evolution have been exploited by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Salmonella enterica and other members of the family Enterobacteriaceae: (i) the selection of mutants with expanded substrate specificity from the plasmid-mediated TEM- and SHV-type β-lactamases, that were already prevalent among Enterobacteriaceae since the 1970s; and (ii) the capture of novelβ-lactamase genes from the environmental metagenome, encoding enzymes that are naturally endowed with ESBL activity. Among the latter enzymes, the CTX-M type β-lactamases have proved by far the most successful in disseminating in the clinical setting and have overall become the most prevalent ESBLs worldwide.
A number of review articles on CTX-M-type β-lactamases have been published in recent years (Bonnet, 2004, Walther-Rasmussen and Hoiby, 2004, Canton and Coque, 2006, Rossolini et al., 2008, Naseer and Sundsfjord, 2011, Canton et al., 2012, Zhao and Hu, 2013). However, the epidemiology of CTX-M-type ESBLs is evolving rapidly, together with knowledge of their structural and functional properties, and clinical significance. The objective of this paper is to provide a concise update on CTX-M-type β-lactamases, with focus on aspects related with structural and functional diversity, epidemiology and clinical significance.
Section snippets
Diversity and origin of CTX-M-type β-lactamases
The CTX-M-type β-lactamases belong in a quite heterogeneous lineage of molecular class A active site-serine β-lactamases, which includes at least six sublineages or groups (CTX-M-1, CTX-M-2, CTX-M-8, CTX-M-9, CTX-M-25 and KLUC, named after the archetypal enzymes of each group) that differ from each other by ≥10% amino acid residues (Fig. 1). Each group, in turn, includes a number of minor allelic variants which differ from each other by one or few amino acid substitutions (≤5% amino acid
Capture and dissemination mechanisms of blaCTX-M genes
Acquired blaCTX-M genes found in clinical isolates of Enterobacteriaceae are generally carried by conjugative plasmids (Carattoli, 2009, Carattoli, 2011, Zhao and Hu, 2013), although in some strains (mostly of Proteus mirabilis but occasionally also of other species) they were found integrated into the chromosome (Coque et al., 2008, Navon-Venezia et al., 2008, Fabre et al., 2009, Coelho et al., 2010, Song et al., 2011, Mahrouki et al., 2012).
Analysis of the genetic environment of acquired bla
Functional properties of CTX-M-type β-lactamases and contribution to β-lactam resistance
The CTX-M-type β-lactamases derive their name from the potent cefotaximase activity, which is a functional hallmark of these enzymes. This feature depends on a peculiar electrostatic environment and flexibility of the catalytic pocket, in combination with other structural elements (e.g. the conserved Arg276 residue, which acts as a mobile electrostatic arm tracking cefotaxime toward the binding site), that allow an efficient recognition and hydrolysis of the bulky cefotaxime molecule with
Epidemiology of CTX-M-producers and clinical impact
Since the first sporadic reports in the late 1980s from Japan, Europe and South America (Matsumoto et al., 1988, Bauernfeind et al., 1990, Bauernfeind et al., 1992), the CTX-M-type ESBLs have experienced a global diffusion, outnumbering and partially replacing the TEM- and SHV-type ESBLs, and becoming overall the most prevalent type of ESBL. For a comprehensive picture of the penetration and globalization of CTX-M-type enzymes occurred during the past two decades the reader may refer to the
Diagnostic issues
Diagnosis of CTX-M-producers may be relevant to molecular epidemiology and infection control. While CTX-M production can be suspected in ESBL producers that exhibit certain resistance profiles (see above), molecular analysis is needed to confirm the presence of a CTX-M-type determinant. Diversity of blaCTX-M genes complicates molecular detection, and various strategies have been proposed, based on multiplex PCR (Woodford et al., 2006, Naas et al., 2007, Pitout et al., 2007, Dallenne et al., 2010
Conclusions
The rapid and extensive dissemination of CTX-M-type ESBLs in clinical and veterinary settings, but also among commensal bacteria of humans and animals and in the environment, is one of the most successful histories of microbial drug resistance observed in the antibiotic era. This success likely depend on the combination of various factors including efficient capture and dispersal of blaCTX-M gene by mobile genetic elements, association of these elements with highly successful bacterial clones,
Acknowledgements
Research on antibiotic resistance mechanisms in the Laboratories of the Authors has been funded by Grants from the European Commission (TROCAR contractHEALTH-F3-2008-223031; TEMPOtest-QC contract HEALTH-2009-241742; EvoTAR contract LSHM-2011-282004), and from the Italian Ministry of University and Research (PRIN 2009, protocol no. 200929YFMK_004).
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