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Review Article

Epidemiology and genetics of CTX-M extended-spectrum β-lactamases in Gram-negative bacteria

Wei-Hua ZhaoDepartment of Microbiology and Immunology, Showa University School of Medicine, Tokyo, JapanCorrespondence[email protected]
&
Zhi-Qing HuDepartment of Microbiology and Immunology, Showa University School of Medicine, Tokyo, Japan
Pages 79-101 | Received 02 Mar 2012, Accepted 03 May 2012, Published online: 15 Jun 2012

Abstract

CTX-M enzymes, the plasmid-mediated cefotaximases, constitute a rapidly growing family of extended-spectrum β-lactamases (ESBLs) with significant clinical impact. CTX-Ms are found in at least 26 bacterial species, particularly in Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis. At least 109 members in CTX-M family are identified and can be divided into seven clusters based on their phylogeny. CTX-M-15 and CTX-M-14 are the most dominant variants. Chromosome-encoded intrinsic cefotaximases in Kluyvera spp. are proposed to be the progenitors of CTX-Ms, while ISEcp1, ISCR1 and plasmid are closely associated with their mobilization and dissemination.

Introduction

Extended-spectrum β-lactamases (ESBLs) are the most influential mechanism for cephalosporin resistance in Enterobacteriaceae, particularly in Escherichia coli and Klebsiella pneumoniae. ESBLs confer resistance to penicillins, broad-spectrum cephalosporins with an oxyimino side chain (cefotaxime, ceftriaxone and ceftazidime) and the oxyimino-monobactam aztreonam, but can be inhibited by serine-type β-lactamase inhibitors as sulbactam, clavulanate and tazobactam (Philippon et al., Citation1989; Bradford, Citation2001). SHV-2 is the first ESBL, identified in a clinical isolate of Klebsiella ozaenae in Germany (Kliebe et al., Citation1985). To date, over 10 families have been documented to be associated with ESBLs, including CTX-M, SHV, TEM, PER, VEB, BES, GES, TLA, SFO and OXA (Paterson and Bonomo, Citation2005).

CTX-M enzymes, the plasmid-mediated acquired cefotaximases from a distinct phylogenetic lineage, constitute a rapidly growing family of ESBLs with significant clinical impact (Bonnet, Citation2004; Cantón and Coque, Citation2006; Livermore et al., Citation2007; Naseer and Sundsfjord, Citation2011). Chromosome-encoded genes of intrinsic cefotaximases in Kluyvera spp. are proposed to be the progenitors of CTX-M family (Humeniuk et al., Citation2002; Olson et al., Citation2005; Decousser et al., 2011). Most of CTX-Ms exhibit powerful activity against cefotaxime and ceftriaxone but not ceftazidime. However, some CTX-Ms, such as CTX-M-15 (Poirel et al., Citation2002a), CTX-M-16 (Bonnet et al., Citation2001) and CTX-M-19 (Poirel et al., Citation2001), exhibit enhanced catalytic efficiencies against ceftazidime.

This article summarizes the epidemiology of CTX-M-producing Gram-negative bacteria and the genetics of CTX-M ESBLs, with a focus on the phylogeny, origin and genetic platforms including ISEcp1, ISCR1 and plasmid.

Epidemiology of CTX-M ESBLs

Occurrence and bacterial hosts

A plasmid-mediated cefotaximase was identified from a clinical isolate of E. coli in Munich, Germany, and designated CTX-M in reference to its hydrolytic activity and the region where it was found (Bauernfeind et al., Citation1990). To date, the numbers of CTX-M variants and the recognized organisms harboring the genes have dramatically increased. At least 109 CTX-M variants, CTX-M-1 to CTX-M-124, have been identified () and assigned in the Lahey database (Jacoby and Bush, Citation2012). The amino-acid sequences of CTX-M-14 and CTX-M-18 and of CTX-M-55 and CTX-M-57 are identical, and CTX-M-118 has been withdrawn. There is no detailed information available for the assigned members CTX-M-70, -73, -100, -103, -115, -119, -120 and -124 so far. In addition, CTX-M-76, -77, -78 and -95 are chromosome-encoded intrinsic cefotaximases in Kluyvera spp., and therefore, they are not counted into the CTX-M family. CTX-M-2, -3 and -37 are plasmid-mediated enzymes but also found on chromosomes in Kluyvera spp. To clarify the differences, the term c-CTX-M is used for such chromosome-encoded CTX-Ms in this article. Of the studied CTX-Ms, at least 19 variants display the enhanced catalytic efficiencies against ceftazidime ().

Table 1.  CTX-M ESBLs and their bacterial hosts.

CTX-Ms have been detected in at least 26 bacterial species, including Acinetobacter baumannii, Aeromonas caviae, A. hydrophila, Citrobacter amalonaticus, C. freundii, C. koseri, E. coli, Enterobacter cloacae, E. aerogenes, E. gergoviae, E. hormaechei, K. pneumoniae, K. oxytoca, Morganella morganii, Proteus mirabilis, Pantoea agglomerans, Providencia rettgeri, P. stuartii, Pseudomonas aeruginosa, Salmonella enterica, Shigella flexneri, S. sonnei, Serratia marcescens, S. liquefaciens, Stenotrophomonas maltophilia and Vibrio cholera ().

CTX-M enzymes as the most prevalent ESBLs in E. coli, K. pneumoniae and P. mirabilis

The high prevalence of CTX-M ESBL genes in Enterobacteriaceae, particularly in E. coli, K. pneumoniae and P. mirabilis, has been documented worldwide (Bonnet, Citation2004; Cantón and Coque, Citation2006), while the CTX-Ms are not prominent in P. aeruginosa and A. baumannii (Zhao and Hu, Citation2010, 2012).

A study on the resistance of Enterobacteriaceae to third-generation cephalosporin was undertaken in 16 British hospitals over a 12-week period (Potz et al., Citation2006). Of 19,252 clinical isolates, CTX-M-producing strains accounted for 1.7%, higher than other ESBLs-producing strains (0.6%) and high-level AmpC-producing strains (0.4%). Particularly, of the resistance isolates of E. coli (n = 574) and Klebsiella spp. (n = 243), the CTX-M-producing strains accounted for 50.9% and 81.9%, respectively, by contrast with other ESBLs-producing strains (15.3% and 11.1%), high-level AmpC-producing strains (7.1% and 0.8%) and non-β-lactamase-producing strains (26.7% and 3.3%).

A rapid occurrence of CTX-M-producing strains in Enterobacteriaceae was documented by several longitudinal surveillances. Of 20,258 E. coli isolates studied in Italy, the prevalence of ESBL-producing strains increased from 0.2% in 1999 to 1.6% in 2003, of which CTX-M-positive strains increased from 12.5% to 38.2% (Brigante et al., Citation2005). Of 1574 P. mirabilis clinical isolates collected in a Taiwanese hospital during 1999–2005, 44 CTX-M-producing strains were detected at a rate of 0.7% in 1999 and approximately 6% after 2002 (Wu et al., Citation2008). Of 11,407 E. coli isolates from urine samples of outpatients in the USA, 107 CTX-M-producing strains were detected at a rate of 0.07% in 2003 and 1.66% in 2008 (Qi et al., Citation2010).

CTX-M-producing strains widespread not only in human but also in animals and in environments. Of 240 E. coli isolates from health and sick pets during 2007–2008 in China, 97 strains (40.4%) harbored ESBL-encoding genes, of which 96 strains were confirmed to be carriers of blaCTX-M genes (Sun et al., Citation2010). Of 16 multi-drug resistant E. coli isolates from river water during 2000–2001 in South Korea, 10 strains harbored CTX-M-14 gene (Kim et al., Citation2008). Of 79 food samples of animal origin in Tunisia, blaCTX-M-1-positive E. coli strains were isolated from 10 samples (Ben Slama et al., Citation2010).

A Japanese group surveyed the spread status of CTX-M genes in nosocomial Gram-negative bacteria collected from 132 geographically distant medical facilities during 2001–2003. Of the 1456 isolates resistant to oxyimino-cephalosporins, 21.8% were found to harbor blaCTX-M genes. The prevalent rates of CTX-Ms in ESBL-producing E. coli, K. pneumoniae and P. mirabilis were 77% (168/218), 56% (50/90) and 99% (71/72), respectively, while the rates of CTX-Ms in ESBL-producing A. baumannii and S. marcescens were 4.5% (4/89) and 7% (10/149), respectively (Shibata et al., Citation2006).

CTX-M-15 and CTX-M-14 as the most dominant variants in CTX-M family

Although the dominant variants of CTX-Ms are geographically different, CTX-M-15 and CTX-M-14 are the most common variants detected worldwide in clinically important pathogens, followed by CTX-M-2, CTX-M-3 and CTX-M-1 (). Conjugative plasmid-mediated horizontal transfer and clonal spread contributed to the increased prevalence.

Of 171 CTX-M-producing E. coli isolates from 11 Canadian medical centers in 2007, the positive rates for CTX-M-15, CTX-M-14, CTX-M-3 and CTX-M-27 were 86.5%, 9.9%, 2.9% and 0.6%, respectively (Peirano et al., Citation2010). Of 202 CTX-M-producing K. pneumoniae isolates from 41 medical centers in Hungary in 2005, 97% were CTX-M-15 producers derived from three genetically distinct clones (Damjanova et al., Citation2008). Of the CTX-M-producers (288 E. coli and 142 K. pneumoniae isolates) collected from 6 provinces in China during 1998–2002, CTX-M-14 was predominantly detected in 77.4% and 52.8% of the isolates, respectively, followed by CTX-M-3 (18.4% and 29.6%), CTX-M-24 (5.6% and 14.1%) and CTX-M-15 (0.7% and 1.4%) (Yu et al., Citation2007). An outbreak of CTX-M-producing S. enterica infection occurred in a university hospital in Algeria during 2008–2009, and all of 200 isolates from 138 patients were CTX-M-15 producers, identified to be a single clone (Naas et al., Citation2011).

Of 44 clinical isolates of CTX-M-producing P. mirabilis from a Taiwanese hospital, CTX-M-14 and CTX-M-3 positive strains accounted for 50% and 40.9%, respectively (Wu et al., Citation2008). Of 71 CTX-M-producing P. mirabilis isolates collected from 132 geographically distant hospitals in Japan, however, 100% of the strains carried the blaCTX-M-2-like genes (Shibata et al., Citation2006). CTX-M-2 was also predominant in C. koseri, accounting for 76.7% of ESBL-producing strains (n = 60) collected from 10 areas throughout Japan in a 5-month period between 2009 and 2010 (Kanamori et al., Citation2011).

Phylogeny, origin and evolution of CTX-M enzymes

Amino-acid identity and phylogeny

The deduced amino-acid sequences of CTX-Ms comprise 291 residues, with the exceptions of CTX-M-11 (282), CTX-M-107 and -108 (288), CTX-M-45 and -109 (289), CTX-M-40, -63 and -106 (290) and CTX-M-110 (292). Based on the phylogenetic tree of amino-acid sequences, CTX-M enzymes may be divided into seven clusters ().

Figure 1.  Phylogenetic tree of CTX-M family based on amino-acid sequences. DNASIS Pro v2.10 (Hitachi Software Engineering Co., Tokyo, Japan) was used to align the amino-acid sequences and construct the phylogenetic tree. The amino-acid sequences were downloaded from GenBank under the accession numbers cited in . The branch lengths are drawn to scale and are proportional to the number of different amino-acid residues. The scale bars of 0.05 and 0.005 represent 5% and 0.5% amino-acid difference, respectively.

Figure 1.  Phylogenetic tree of CTX-M family based on amino-acid sequences. DNASIS Pro v2.10 (Hitachi Software Engineering Co., Tokyo, Japan) was used to align the amino-acid sequences and construct the phylogenetic tree. The amino-acid sequences were downloaded from GenBank under the accession numbers cited in Table 1. The branch lengths are drawn to scale and are proportional to the number of different amino-acid residues. The scale bars of 0.05 and 0.005 represent 5% and 0.5% amino-acid difference, respectively.

CTX-M-3 cluster includes 42 members, sharing 97.6–99.7% identity in amino-acid sequences. The other clusters are as follows: CTX-M-14 cluster, 38 members, 97.3–99.7% identity; CTX-M-2 cluster, 16 members, 95.2–99.7% identity; CTX-M-25 cluster, 7 members, 98.6–99.7% identity; CTX-M-8 cluster, 3 members, 97.9–99.7% identity; CTX-M-64 cluster, 2 members, 95.9% identity. There is only one member in CTX-M-45 cluster. Among CTX-M variants, CTX-M-4 and CTX-M-45 are most divergent with 91 amino-acid substitutions.

Variations of amino-acid sequences

Based on the central positions in phylogenetic tree (), CTX-M-2, -3, -8, -14, -25, -45 and -64 are chosen as the representative enzymes in each cluster. The amino-acid sequences of the seven enzymes are aligned, and numbered according to the standard numbering scheme for the class A serine β-lactamases, giving the active site serine residue the Ambler number 70 (Ambler et al., Citation1991) (). The sequences of CTX-M variants are then compared with their representative in each cluster (). In the CTX-M-3 cluster, for example, a single amino-acid is substituted between CTX-M-3 and CTX-M-15, -22, -42, -54, -62, -66, -72 or -80, while 5 amino-acids are substituted between CTX-M-3 and CTX-M-58.

Table 2.  Amino acid substitutions of CTX-M variants compared to their representative enzymes.

Figure 2.  Comparison of amino-acid sequences of seven representative enzymes in the CTX-M family. Amino-acids are numbered according to the standard numbering scheme for the class A serine β-lactamases, giving the active site serine residue the Ambler number 70. Dots indicate identical amino-acids compared to CTX-M-2. Deletion mutations are expressed with short lines. The underlined amino-acids, 70SXXK73, 107P, 130SDN132, 143GG144, 166E and 234KXG236, represent the conserved residues in typical class A serine β-lactamases.

Figure 2.  Comparison of amino-acid sequences of seven representative enzymes in the CTX-M family. Amino-acids are numbered according to the standard numbering scheme for the class A serine β-lactamases, giving the active site serine residue the Ambler number 70. Dots indicate identical amino-acids compared to CTX-M-2. Deletion mutations are expressed with short lines. The underlined amino-acids, 70SXXK73, 107P, 130SDN132, 143GG144, 166E and 234KXG236, represent the conserved residues in typical class A serine β-lactamases.

Origin of CTX-M family

In the family Enterobacteriaceae, the genus Kluyvera is a relatively new member, which has been isolated from various clinical specimens and regarded as a potentially virulent pathogen (Sarria et al., Citation2001). Some Kluyvera spp. harbor chromosome-encoded intrinsic genes of cefotaximases which are closely associated with CTX-Ms (Decousser, et al., 2001; Humeniuk et al., Citation2002; Rodríguez et al., Citation2004). Generally, Kluyvera spp. are susceptible to cefotaxime in despite of the presence of naturally occurring cefotaximases. However, the recombinant clones of E. coli with Kluyvera-derived cefotaximase genes exhibited a significant increase in resistance to cefotaxime (Decousser et al., Citation2001; Humeniuk et al., Citation2002; Rodríguez et al., Citation2004), suggesting that a proper genetic platform is necessary for the gene expression. The chromosome-encoded cefotaximases identified in Kluyvera spp. include KLUA, KLUG, KLUY, KLUC, c-CTX-M-2, c-CTX-M-3, c-CTX-M-37, c-CTX-M-76, c-CTX-M-77, c-CTX-M-78 and c-CTX-M-95. All of them comprise 291 amino-acid residues. An aspartate aminotransferase-encoding gene is found commonly upstream of these chromosomal bla genes, which is replaced by ISEcp1 or ISCR1 in the plasmid-harbored blaCTX-M genes (see the details under next section).

KLUA-1 to -5 and -8 to -12 (GenBank accession no. AJ272538, AJ251722, AJ427461, AJ427462, AJ427463, AJ427465, AJ427466, AJ427467, AJ427468, AJ427469) are a group of chromosomal cefotaximases identified in K. ascorbata, with minor variations (<5%) in their amino-acid sequences (Humeniuk et al., Citation2002). KLUA-2 shares 100% identity with plasmid-mediated CTX-M-5. CTX-M-2 and CTX-M-3 originally identified on plasmids were also found on the chromosomes of K. ascorbata (Rodríguez et al., Citation2004; Lartigue et al., Citation2006). The immediate upstream- and downstream-sequences of blaKLUA-1 and plasmid-mediated bla genes in CTX-M-2 cluster (blaCTX-M-2, -4, -5, -6, -7,-44) share 85 to 100% identities (Di Conza et al., Citation2002; Humeniuk et al., Citation2002). The architectures of the flanking regions corresponding to c-CTX-M-3 and plasmid-mediated CTX-M-3 are identical, including a 128 bp immediate upstream region and the first 373 bp of the downstream region of the bla gene (Rodríguez et al., Citation2004). The c-CTX-M-76, -77 and -95 (AM982520, AM982521, FN813245) identified in K. ascorbata also share high identities with the enzymes in CTX-M-2 cluster.

KLUY-1 to -4 (AY623932, AY623935, AY623934, AY623933) are a group of chromosomal cefotaximases identified in K. Georgiana (Olson et al., Citation2005). They share high homology with the enzymes in CTX-M-14 cluster. Typically, KLUY-1 exhibits 100% amino-acid identity with CTX-M-14. The upstream- and downstream-sequences of blaKLUY and blaCTX-M-9, -13, -14 also share consistent identity. A 42 bp upstream region of blaCTX-M-14 is identical to the corresponding region of blaKLUY genes. A 347 bp downstream region of blaCTX-M-9 and blaCTX-M-13 shares 95.7–98.6% identities with the corresponding region of blaKLUY genes (Olson et al., Citation2005).

KLUG-1 (AF501233) and c-CTX-M-78 (AM982522) are the chromosomal cefotaximases identified in K. Georgiana. KLUG-1 shares 99% amino-acid identity with the plasmid-mediated CTX-M-8 (Poirel et al., Citation2002b). The c-CTX-M-78 possesses high homology with the known members of CTX-M-25 cluster, sharing 95.2–96.2% identities (Rodríguez et al., Citation2010).

CTX-M-37 was also found on the chromosome of K. cryocrescens (FN813246), suggesting the c-CTX-M-37 as an origin of CTX-M-3 cluster. KLUC-1 (AY026417) and KLUC-2 (EF057432), with a single amino-acid substitution, are two chromosome-encoded cefotaximases identified in K. cryocrescens (Decousser et al., Citation2001). KLUC-1 and -2 are diverse from the known CTX-Ms, sharing only 87.6% identity with CTX-M-3. Notably, KLUC-2 was also identified on a plasmid carried by a clinical isolate of E. cloacae, indicating the transfer of blaKLUC from chromosome to the plasmid (Petrella et al., Citation2008). We would like to suggest the plasmid-mediated KLUC-2 as a novel cluster or member of CTX-M family.

CTX-M-64 shows a chimeric sequence of both CTX-M-14 (central portion) and CTX-M-15 (N- and C-terminal moieties), suggesting an origination owing to homologous recombination between the blaCTX-M-14 and -15 genes (Nagano et al., Citation2009).

Taken together, the origins of the acquired CTX-Ms in various clusters can be traced back to the intrinsic cefotaximase genes harbored by Kluyvera spp., of which the CTX-M-2 cluster appears to be derived from K. ascorbata, the CTX-M-14, CTX-M-8 and CTX-M-25 clusters from K. georgiana, while the CTX-M-3 cluster from both K. ascorbata and K. cryocrescens ().

Figure 3.  Identification of intrinsic cefotaximase genes in Kluyvera spp. as the original sources of acquired CTX-Ms based on their amino-acid identities and the homologies of neighboring sequences of the associated genes. c-CTX-M, CTX-M identified on chromosome of Kluyvera spp.; p-KLUC-2, KLUC-2 identified on plasmid in a clinical isolate of Enterobacter cloacae.

Figure 3.  Identification of intrinsic cefotaximase genes in Kluyvera spp. as the original sources of acquired CTX-Ms based on their amino-acid identities and the homologies of neighboring sequences of the associated genes. c-CTX-M, CTX-M identified on chromosome of Kluyvera spp.; p-KLUC-2, KLUC-2 identified on plasmid in a clinical isolate of Enterobacter cloacae.

Genetic platforms of CTX-M enzymes

ISEcp1

Insertion sequences (ISs) are the smallest transposable elements (<2.5 kb) capable of independent transposition in an organism, thereby causing insertion mutations and genome rearrangements (Mahillon and Chandler, Citation1998). ISs play three basic roles in bacteria: encoding a transposase which makes a genetic element mobile; providing promoters to activate silent genes or enhance expression of downstream determinants; moving IS-mobilized genes among integrons, transposons, plasmids and chromosomes, thereby greatly increasing the opportunity a resistance determinant becomes transferable.

Of the genetic platforms associated with CTX-Ms, ISEcp1 is one of the most important elements (). ISEcp1 was first identified on the plasmid pST01 in E. coli strain 79 (AJ242809), hence its name (Stapleton, Citation1999). ISEcp1 is composed of an orf encoding a transposase with 420 amino-acids and two imperfect and inverted repeats. ISEcp1 can mobilize the downstream-located blaCTX-M gene and provide a promoter for its expression (Karim et al., Citation2001; Cao et al., Citation2002; Poirel et al., Citation2003, 2005; Dhanji et al., Citation2011b).

Table 3.  Genetic platforms of CTX-M enzymes.

Co-existence of ISEcp1 and blaCTX-M at a high rate in CTX-M-producing E. coli isolates is well documented. ISEcp1 was identified upstream of blaCTX-M genes in 86.9% of the isolates (93/107) recovered from health and sick pets in China, and no major clonal relatedness was observed (Sun et al., Citation2010). Similarly, ISEcp1 was identified upstream of blaCTX-M-14 in 91.4% of the clinical isolates (32/35) in Korea (Kim et al., Citation2011), and upstream of blaCTX-M-1 in 69.2% of the isolates (9/13) from food samples in Tunisia (Ben Slama et al., Citation2010). In addition, variations of ISEcp1 were also observed. ISEcp1B, originally identified upstream of a blaCTX-M-19 gene cassette (AF458080), differs from ISEcp1 by three nucleotide substitutions (Poirel, et al., 2003). Of the 174 ISEcp1-like and blaCTX-M-15 complex from E. coli isolates, the intact ISEcp1, truncated ISEcp1 with various lengths and a 24 bp remnant of ISEcp1 accounted for 62%, 33.3% and 4.6%, respectively (Dhanji et al., Citation2011b). Notably, ISEcp1 was also detected upstream of chromosomal blaCTX-M-2 genes in 4 P. mirabilis isolates in Japan (Harada et al., Citation2012), highlighting the ISEcp1-mediated movement of blaCTX-M genes between plasmids and chromosomes.

ISEcp1-blaCTX-M-IS903 () and ISEcp1-blaCTX-M-orf477 () are two major genetic platforms. In some cases, ISEcp1-mobilized blaCTX-M is inserted in a class 1 integron (). IS903 (V00359) encodes a transposase with 307 amino-acids and was originally found on a kanamycin resistance transposon Tn903 (Oka et al., Citation1981). IS903 and IS903-like elements, such as IS903C and IS903D, are located downstream of blaCTX-M genes (), including blaCTX-M-14-like genes (blaCTX-M-14, -16, -17, -19, -24, -27, -65, -90, -93, -98, -102, -104, -105, -121, -122) and blaCTX-M-3-like gene (blaCTX-M-54). orf477 encodes a protein of 158 amino-acids with unknown function and the orf477 and orf477-like elements were found downstream of plasmid-harbored blaCTX-M-3-like genes (blaCTX-M-1, -3, -15, -22, -32, -53, -55, -66), blaCTX-M-89 and blaCTX-M-64 (). The orf477 was also identified downstream of the chromosomal blaCTX-M-3 in K. ascorbata, of the chromosomal blaKLUY-1, -2, -3, -4 in K. georgiana, and of the chromosomal blaCTX-M-37 (FN813246) in K. cryocrescens (Rodriguez et al., 2004; Olson et al., Citation2005), footnoting the ISEcp1-mediated transfer of blaCTX-M genes together with the orf477 from the chromosomes of Kluyvera spp. to plasmids.

Figure 4.  Typical genetic platforms of CTX-M enzymes. A & B: the blaCTX-M gene cassettes bracketed upstream by ISEcp1/ISEcp1-like and downstream by IS903/IS903-like (A) or orf477/orf477-like (B); C: blaCTX-M genes associated with class 1 integron-ISEcp1; D & E: blaCTX-M genes associated with class 1 integron-ISCR1 complex. CS, conserved segment; intI, integrase gene; qacE▵1, quaternary ammonium resistance gene; sul1, sulphonamide resistance gene; 3′-CS2, the second copy of 3′-conserved segment.

Figure 4.  Typical genetic platforms of CTX-M enzymes. A & B: the blaCTX-M gene cassettes bracketed upstream by ISEcp1/ISEcp1-like and downstream by IS903/IS903-like (A) or orf477/orf477-like (B); C: blaCTX-M genes associated with class 1 integron-ISEcp1; D & E: blaCTX-M genes associated with class 1 integron-ISCR1 complex. CS, conserved segment; intI, integrase gene; qacE▵1, quaternary ammonium resistance gene; sul1, sulphonamide resistance gene; 3′-CS2, the second copy of 3′-conserved segment.

Class 1 integron-ISCR1 complex

Integrons are defined as mobile DNA elements that can capture genes by site-specific recombination (Stokes and Hall, Citation1989). A typical class 1 integron consists of a 5′ conserved segment (5′-CS), a variable region and a 3′ conserved segment (3′-CS). The 5′-CS consists of the gene encoding integrase (intI1), the site adjacent to intI1 for the insertion of captured genes (attI), and a promoter region (Pc). The 3′-CS often consists of a partially deleted qac gene (qacEΔ1) fused to a sul1 gene, and confers resistance to antiseptics and sulfonamide, respectively. Class 1 integrons play a critical role in acquiring and spreading metallo-β-lactamases (Mazel, Citation2006; Zhao and Hu, Citation2011a,b). The role of integrons in CTX-M gene acquisition and dissemination, however, is still unclear. The physical link of some blaCTX-M genes with class 1 integron-ISEcp1 complex () and class 1 integron-ISCR1 complex (, ) indicates a possible association among the three genetic elements.

ISCR1 is another important element in the genetic platforms associated with the mobilization and dissemination of CTX-M genes (Rodriguez-Martinez et al. Citation2006; Toleman et al., Citation2006). Common region 1 (CR1) was first found as element associated with but distinct from class 1 integrons (Stokes et al., Citation1993). The CR1 element was renamed ISCR1 because it possesses the key motifs of IS91-like element and accommodates orf513 gene which codes a putative transposase of 513 amino-acids (Toleman et al., Citation2006). ISCR1 is particularly important for CTX-M-2 and CTX-M-9 genes (). In most instance, the ISCR1-blaCTX-M-2 is located between a typical class 1 integron and a fuse type of orf3Δ and qacEΔ1/sul1 (, ). Notably, the genes harbored by class 1 integrons in their variable regions, such as blaOXA-2, aacA4, cmlA and dfr, are also associated with bacterial resistance to β-lactam, aminoglycoside, chloramphenicol and trimethoprim, respectively.

Molecular epidemiological study performed in Argentine during 1993–2000 showed that class 1 integron-ISCR1 complex was adjacent to blaCTX-M-2 in all the CTX-M-2 producers (n = 35), including Acinetobacter spp., E. cloacae, E. coli, K. pneumoniae, P. mirabilis, P. aeruginosa, S. enterica and S. marcescens, while only 1.5% of the blaCTX-M-2-negative isolates (n = 65) harbored ISCR1 (Arduino et al., Citation2003). These data strongly implicate the association of ISCR1 with the emergence and dissemination of blaCTX-M-2 gene. In addition, ISCR1 is also related to blaCTX-M-59, -74, -75 (members of CTX-M-2 cluster) and blaCTX-M-1, -9, -14 ().

Other IS and phage-related sequences

Besides ISEcp1, IS903 and ISCR1 described above, IS1, IS5, IS10, IS26, IS50A, IS1294, IS1326, IS3000, IS4321 and IS6100 were also found to be adjacent to blaCTX-M genes (). In some cases, several IS elements co-existed in a gene complex, for example, intI1-dfrA12-orfF-aadA2-qacEΔ1-sul1-ISCR1-IS6100-ISCR1-ISEcp1Δ-blaCTX-M-14-IS903D (Bae et al., Citation2008). Such heterogeneity may be explained by a continuously recombinatorial exchange of gene cassettes, denoting the sophisticated genetic rearrangement strategies that organisms acquire and dispense resistance genes.

A 12.2-kb DNA fragment containing blaCTX-M-10 gene in plasmid pRYCE21 was cloned from K. pneumoniae, and further detected in other bacterial species including E. coli, E. cloacae and E. gergoviae. Analysis of the sequence showed a phage-related 3.5-kb element immediately upstream of the blaCTX-M-10 gene cassettes. This phage-related fragment corresponds to four orfs, of which orf2, orf3 and orf4 display homology to the genes of conserved phage tail proteins (Oliver et al., Citation2005). Although there is a limited report on phage-related CTX-M genes, this finding indicates that phages may also function as a tool for blaCTX-M-associated genetic elements to become transferable.

Plasmids

The movement of IS-mobilized genes between chromosomes and plasmids greatly increase the opportunity a resistance determinant becomes transferable. Particularly, conjugative plasmid is one of the most important mechanisms for intra-species, inter-species and inter-genus gene transfers.

Plasmids are usually classified on their incompatibility (Inc), defined as the inability of two plasmids to be propagated stably in the same bacterial strain; thus, only compatible plasmids can be rescued in transconjugants (Novick et al., Citation1976). At least 29 Inc groups have been recognized among plasmids of enteric bacteria, including IncFI, IncFII, IncFIII, IncFIV, IncFV, IncFVI, IncI1, IncI2, IncIy, IncHI1, IncHI2, IncHI3, IncA/C, IncB, IncD, IncJ, IncK, IncL/M, IncN, IncO, IncP, IncS, IncT, IncU, IncV, IncW, IncX, IncY and com9 (Novick et al., Citation1976; Couturier et al., Citation1988). The IncFII, IncA/C, IncL/M, and IncI1 plasmids show the highest occurrence among the typed resistance plasmids (Carattoli, Citation2009).

Molecular epidemiological studies have revealed a close and significant linkage of blaCTX-M genes to plasmids, mainly belonged to IncF, IncI, IncN, IncHI2, IncL/M and IncK groups (). The IncF group (FIA, FIB and FII) is the most prevalent in transmitting blaCTX-M-15 genes, while IncF, IncK and IncI1 are closely related to the widespread of blaCTX-M-14 genes. In addition, the blaCTX-M-1 gene is dominantly harbored by IncN and IncI1, blaCTX-M-3 gene by IncL/M and IncI1, and blaCTX-M-9 gene by IncHI2.

Table 4.  Plasmids associated with the spread of CTX-M genes.

Unlike the plasmids with broad host range, such as IncP, IncA/C and IncQ, IncF plasmids are limited by host range to the genera of Enterobacteriaceae (Toukdarian, Citation2004), footnoting the high prevalence and widespread of CTX-M genes in Enterobacteriaceae, but not in Acinetobacter and Pseudomonas.

Various resistance genes frequently co-exist on a plasmid, facilitating the dissemination of resistance determinants and the survival of bacteria under the pressure of various antibiotics. For example, plasmid pEK499 (a fusion of type FII and FIA replicons) identified in a UK variant of the internationally prevalent E. coli O25:H4-ST131 lineage is confirmed to harbor 10 resistance genes, conferring resistance to seven antibiotic classes, β-lactams (blaCTX-M-15, blaOXA-1, blaTEM-1), aminoglycoside (aac6′-Ib-cr, aadA5), macrolides (mph(A)), chloramphenicol (catB4), tetracycline (tet(A)), trimethoprim (dfrA7) and sulfonamide (sul1) (Woodford et al., Citation2009).

Secondary chromosomal integration

Most of the blaCTX-M genes are harbored by plasmids and the secondary chromosomal insertions of blaCTX-M genes are also confirmed, particularly in P. mirabilis. Of 25 clinical isolates of CTX-M-producing P. mirabilis collected in Korea, 21 strains harbored blaCTX-Ms on their chromosomes (Song et al., Citation2011). The genes of blaCTX-M-25 and-41 were also found on the chromosomes of P. mirabilis in Israel (Navon-Venezia et al., Citation2008).

In addition, chromosomal integration of blaCTX-M-15 gene was reported in E. coli, K. pneumoniae and S. enterica (Coque et al., Citation2008; Coelho et al., 2010; Fabre et al., Citation2009). Chromosomal blaCTX-M-9 was observed in one strain of 30 E. coli isolates collected in Barcelona during 1996–1999 (García et al., Citation2005).

Conclusion

Plasmid-mediated CTX-M enzymes are the most prevalent ESBLs, particularly in E. coli, K. pneumoniae and P. mirobilis. At least 109 members in CTX-M family are identified and can be divided into seven clusters based on their phylogeny. CTX-M-15 and CTX-M-14 are the most dominant variants in the family, followed by CTX-M-2, CTX-M-3 and CTX-M-1.

The CTX-M genes can be traced back to the chromosome-encoded cefotaximas genes in Kluyvera spp., strongly indicating that the plasmid-mediated CTX-M enzymes are originally from Kluyvera. Multiple genetic elements, especially ISEcp1 and ISCR1, are involved in the mobilization of blaCTX-M genes from the chromosomes to plasmids. Conjugative plasmids are responsible for the transfer of the blaCTX-M genes to new hosts, while the properties of plasmid incompatibility and host range are closely associated with the high prevalence and widespread of the CTX-M genes in Enterobacteriaceae, but not in Acinetobacter and Pseudomonas.

Declaration of interest

This work was supported by a grant (No. 24591489) from the Ministry of Education, Culture, Sports, Science and Technology, Japan and by a grant from Showa University Medical Foundation, Tokyo, Japan.

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