JAC Advance Access originally published online on June 26, 2007
Journal of Antimicrobial Chemotherapy 2007 60(3):470-482; doi:10.1093/jac/dkm226
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Review |
Class A carbapenemases
Department of Clinical Microbiology, 9301, Rigshospitalet, National University Hospital, Copenhagen, Denmark
* Correspondence address. Department of Clinical Microbiology, 9301, Juliane Mariesvej 22, DK-2100 Copenhagen O, Denmark. Tel: +45-26-37-76-60; Fax: +45-35-45-64-12; E-mail: jawalras{at}mail.tele.dk
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Abstract |
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Top
Abstract
Class A ß-lactamasesCarbapenems, such as imipenem and meropenem, are most often used to treat infections caused by enterobacteria that produce extended-spectrum ß-lactamases, and the emergence of enzymes capable of inactivating carbapenems would therefore limit the options for treatment. Carbapenem resistance in Enterobacteriaceae is rare, but class A ß-lactamases with activity against the carbapenems are becoming more prevalent within this bacterial family.
The class A carbapenemases can phylogenetically be segregated into six different groups of which four groups are formed by members of the GES, KPC, SME, IMI/NMC-A enzymes, while SHV-38 and SFC-1 each separately constitute a group.
The genes encoding the class A carbapenemases are either plasmid-borne or located on the chromosome of the host. The blaGES genes reside as gene cassettes on mainly class I integrons, whereas the blaKPC genes and a single blaIMI-2 gene are flanked by transposable elements on plasmids.
Class A carbapenemases hydrolyse penicillins, classical cephalosporins, monobactam, and imipenem and meropenem, and the enzymes are divided into four phenotypically different groups, namely group 2br, 2be, 2e and 2f, according to the Bush–Jacoby–Medeiros classification system. Class A carbapenemases are inhibited by clavulanate and tazobactam like other class A ß-lactamases.
Keywords: class A ß-lactamases , carbapenem resistance , Enterobacteriaceae , Pseudomonas aeruginosa
ß-Lactamases are bacterial enzymes that protect the organisms against the lethal actions of ß-lactam antibiotics, such as penicillins, cephalosporins and carbapenems, by breaking down the indispensable ß-lactam bond in the antibiotics rendering the drugs antimicrobially inert.1 The ß-lactamases are considered as the primary cause of bacterial resistance to these drugs.2
Based on amino acid sequence identities, ß-lactamases can be divided into four disparate molecular classes, labelled A, B, C and D.3–5 Class A, C and D ß-lactamases use a catalytically active serine residue for inactivation of the ß-lactam drug,6 whereas the molecular class B enzymes are metalloenzymes that require zinc as a metal cofactor for their catalytic activities.
Carbapenems, such as imipenem and meropenem, diffuse easily into bacteria7,8 and have a very broad spectrum of activity as the drugs are active against many Gram-negative, Gram-positive and anaerobic bacteria.9,10 The targets of carbapenems are the penicillin-binding proteins (PBPs).8,11
MIC breakpoints for imipenem and meropenem resistance in members of the Enterobacteriaceae and in non-fastidious Gram-negative pathogens, such as Pseudomonas aeruginosa, have been established by the CLSI (formerly NCCLS) as 
16 mg/L while the CLSI susceptibility breakpoints were defined as 
4 mg/L.
Enterobacteriaceae and P. aeruginosa have a plethora of mechanisms to elude the action of carbapenems. Carbapenem resistance in Enterobacteriaceae can be mediated by metallo-ß-lactamases, but enterobacteria carrying genes encoding these enzymes are not always resistant to the carbapenems.12 Carbapenem resistance in Enterobacteriaceae can also be conferred by class A carbapenemases (this review) or on rare occasions by OXA-type carbapenemases.13 Other resistance mechanisms are attributed to altered affinity of PBPs for carbapenems,14,15 increased efflux of the ß-lactam antibiotics,16,17 decreased permeability of the outer membrane,15–19 or to a combination of reduced permeability and high-level production of a ß-lactamase,20–26 typically a class C ß-lactamase.
The carbapenems are recommended as first-line therapy for severe infections caused by Enterobacteriaceae producing extended-spectrum ß-lactamases (ESBLs),27 and the emergence of carbapenem-resistant enterobacteria is therefore worrisome as the antimicrobial armamentarium consequently is restricted.
In P. aeruginosa, class B enzymes account for most of the resistance to carbapenems.12 However, loss of the outer membrane protein, OprD, overexpression of drug efflux pumps and combinations thereof with hyperproduction of the chromosomal class C ß-lactamase also play important roles in the resistance to carbapenems.28–31 Resistance to imipenem seems, however, not to be mediated solely by efflux pumps.32
Another microorganism of major concern is Acinetobacter baumannii which displays a high incidence of resistance to carbapenems owing to the expression of OXA-type carbapenemases.13,33
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Class A ß-lactamases |
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Class A ß-lactamases appear to be the most diverse and widely distributed class of the ß-lactamases as the encoding genes have been found in several bacterial phyla, such as Actinobacteria, Bacteroidetes, Cyanobacteria, Firmicutes and Proteobacteria, including
-, ß- and 
-proteobacteria. The genes do not reside in all genera of these phyla. A multiple sequence alignment of the class A ß-lactamases shows that the enzymes have three highly conserved active site elements in common. The first element is the tetrad, Ser70-X-X-Lys, where X represents a variable residue, containing the active-site serine (Ser70 according to the consensus numbering for class A ß-lactamases34). The second motif, the invariable Ser130-Asp-Asn, is equivalent to the variable Ser-X-Val/Ile element in class D ß-lactamases and Tyr-Ala/Ser-Asn in class C ß-lactamases, while the Lys234-Thr/Ser-Gly triad is common to the vast majority of serine-active ß-lactamases. Another conserved residue in class A ß-lactamases is Glu166 which acts as a general base in the acylation step.35
Many class A ß-lactamases are very efficient in hydrolysing benzylpenicillin and ampicillin, and consequently, the enzymes have been characterized primarily as penicillinases. According to their functional properties, ß-lactamases are divided into different groups.36 Class A ß-lactamases are assigned to the functional group 2 which is segregated into several subgroups. The members of Bush group 2 generally hydrolyse penicillins and classical cephalosporins efficiently, and most of the enzymes are effectively inhibited by clavulanic acid.36
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Clusters of class A carbapenemases |
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A phylogenetic analysis of class A carbapenemases together with other class A ß-lactamases from bacteria belonging to different phyla shows that the carbapenemases form six distantly related branches (Figure 1), and the clusters share amino acid sequence identities ranging from 32% to 70%. The high divergence among the groups of class A carbapenemases suggests that the clusters may have derived from different ancestors.
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The GES enzymes |
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In 1998, a Klebsiella pneumoniae isolate was recovered in a French hospital from an infant that previously had been hospitalized in French Guiana.37 The ß-lactamase characterized from this clinical strain was accordingly named GES-1 (Guiana extended-spectrum), and at present, the GES family enzymes comprise nine different members (Table 1) of which only four, GES-1, -2, -4 and -5, show a measurable enzymatic activity against carbapenems. However, the carbapenemase activity of GES-1 is so low that it seems reasonable to consider the enzyme as an ESBL rather than a carbapenemase. In this review, we have adopted the nomenclature of the GES enzymes accordingly to the Lahey Clinic web site (http://www.lahey.org/Studies). The enzymes of the GES family differ from each other by one to four amino acid substitutions. At present, the phylogenetically closest related ß-lactamase to the GES family enzymes is BEL-1 from P. aeruginosa38 with identities ranging from 50% to 51%.
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The GES enzymes have mainly been found in P. aeruginosa, but the enzymes have also been observed in members of Enterobacteriaceae (Table 1). Isolates producing GES enzymes with carbapenemase activity have been collected predominantly in Europe, South Africa and the Far East (Table 1).
In March–July 2000, an outbreak of clonally related GES-2-producing P. aeruginosa isolates occurred in Republic of South Africa46 while an outbreak involving an endemic strain of K. pneumoniae expressing GES-5 took place in Korea in 2004.60
Apart from the blaGES-7 gene in an Escherichia coli isolate described by Galani et al.,54 the blaGES genes have all been found as gene cassettes on integrons. The E. coli isolate which harbours the chromosomally located blaGES-7 gene is so far the only blaGES gene that has not been identified on an integron.54 Closer investigations on the genetic environment of the blaGES-7 gene have not been published.
From some clinical isolates, the resistance phenotype associated with a GES enzyme could be transferred by conjugation to recipients45–47,49,50,52,55,56,59,60,62 while others were not successful under the experimental conditions used.37,43,48–50 The conjugal transfer may indicate that the blaGES-carrying integrons are present on transferable plasmids. In one instance, the resistance phenotypes were transferred to a recipient by electroporation but not by conjugation37 which may signify that the blaGES-1 integron is located on a non-transferable plasmid. Other isolates appear to have the blaGES-carrying integrons inserted into the chromosome of the host.40,54,57,58
The gene cassettes coding for the GES enzymes were examined by an in silico analysis. The results show that the cassettes characterized in the isolates collected in Europe and South Africa differ only in the structural genes for the GES enzymes. These cassettes are 1020 bp in length, as opposed to the 929 bp long cassettes in the four South American isolates.37,42 The reduced length is caused by identical truncations of the 59 base elements (bes) suggesting that the four cassettes may have a common origin. No data have been published on the blaGES-1 gene cassette in the P. aeruginosa isolate from Argentina43 and consequently it is unknown how long the gene cassette in fact is.
Except for differences in the blaGES-3 and blaGES-4 genes, the two GES-encoding cassettes described in K. pneumoniae isolates from Japan47,48 are identical, but marginally different from the other analogous cassettes.
Owing to the differences between the 59 bes of the GES encoding cassettes, it is conceivable that the blaGES genes have been mobilized from their ancestor on at least two separate occasions in different geographic locations.
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The KPC enzymes |
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The second group encompasses the KPC enzymes (acronym of K. pneumoniae carbapenemase). The four variants that up to now have been described all possess carbapenemase activity and they differ from each other by one to three amino acid substitutions. The nearest phylogenetically related enzyme to the KPCs is another class A carbapenemase, SFC-1, from Serratia fonticola (Figure 1) with an identity of roughly 61%.
Despite the fact that KPC refers to the species in which the KPC-1 enzyme was originally identified, members of this group have also been found in several other enterobacteria and in P. aeruginosa (Table 2). The vast majority of these KPC producers has been collected in the Northeastern parts of USA (Table 2).
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Carbapenem-resistant klebsiellae were not reported in a US nationwide surveillance study from 1998 to 2001.81 Ensuing nationwide or citywide (New York City) survey studies of K. pneumoniae collected from different hospitals showed that the incidence of blaKPC-positive isolates has risen gradually.74,82–86 Most of the blaKPC-carrying isolates in each individual study belonged to the same ribotype.82,85
A screening investigation during September–October 2004 of E. coli, Enterobacter spp. and K. pneumoniae collected from four hospitals in Brooklyn, New York City, showed that none of the E. coli or Enterobacter spp. isolates carried a blaKPC gene, whereas 24% of the K. pneumoniae isolates possessed a blaKPC-2 or blaKPC-3 gene.84 The majority (88%) of the blaKPC-carrying isolates belonged to the same ribotype.84 To date, KPC-producing enterobacteria in USA have been reported from North Carolina, New Jersey, Maryland, Pennsylvania, Massachusetts, Delaware, Arkansas, Ohio, Virginia, New York and New York City.
An outbreak of carbapenem-resistant K. pneumoniae happened in 2000–01 in a Manhattan hospital of New York.77 Most of the isolates were found to be genetically related and produced KPC-3.
Two outbreaks involving imipenem-resistant K. pneumoniae occurred in continuation of each other (2003–04) at two hospitals in Brooklyn, New York City.83 All the isolates carried the KPC-2 carbapenemase and the majority of the isolates belonged to the same ribotype.83 In 2004, a major outbreak of a clonal KPC-2-producing K. pneumoniae occurred in a medical centre in New York City and this clone has subsequently become endemic in the center.65 The KPC-2-producing K. pneumoniae clone was later found in a medical centre in Mineola, NY,65 which is indicative of clonal expansion. Clonal spread between two hospitals has also been reported for KPC-2-producing E. coli found in New York City and Cleveland, OH, USA.65
These facts imply that the KPC determinants have the potential to disseminate rapidly among human pathogens. The emergence of carbapenem resistance in enterobacteria is worrisome because the carbapenem resistance often may be associated with resistance to many ß-lactam and non-ß-lactam antibiotics, and this will eventually limit effective therapeutic regimens.
The prevalence of KPC-producing isolates may be clinically unrecognized because several factors can complicate their detection. In the absence of other mechanisms, the KPC carbapenemases may not confer resistance to carbapenems but only reduced susceptibility74,84 and some phenotypic tests may suggest KPC producers are ESBL producers.74 The presence of carbapenem resistance in K. pneumoniae is sometimes overlooked when automated susceptibility testing systems using low inocula are employed.83,84,87 These difficulties consequently imply that the incidence of KPC-producing K. pneumoniae isolates may be underestimated and an inaccurate identification of carbapenem-resistant K. pneumoniae may also have fatal consequences.
The observations of blaKPC genes in isolates from Israel and Columbia69,72 are a matter of concern as the infected patients from whom the isolates were recovered had no records of recent travel to the eastern parts of USA. These findings indicate that blaKPC genes from a common but unknown ancestor may have been mobilized in these areas or that blaKPC-carrying microorganisms may have been transferred passively from the United States by other vectors. There is no published data on travels outside of P.R. China for the patients from whom the KPC-2-producing isolates were collected.71,76
The genes encoding the KPC carbapenemases all appear to be plasmid-borne, apart from the blaKPC-2 in P. aeruginosa (Table 2). None of the genes has, however, been found in a gene cassette, owing to the lack of the characteristic core site of the 59 be. Instead, the blaKPC genes are associated with mobile elements. Identical sequences coding for a putative IS1-like ATP-binding protein have been found upstream from the blaKPC-2 genes in K. pneumoniae72 and Salmonella enterica.75 Apart from a deletion of six nucleotides resulting in a loss of two amino acids, a partial but otherwise identical sequence of the gene is also found upstream from the blaKPC-2 gene in Klebsiella oxytoca.70
Downstream from the blaKPC-1 and blaKPC-2 genes in K. pneumoniae and S. enterica,63,72,75 the 3'-end of a tnp gene was identified. Owing to lack of sequence data, it is not known whether any of the other blaKPC genes have the same genetic environment.
The genetic contexts of the blaKPC genes were studied by in silico analyses and the investigations showed that the non-coding region downstream from the blaKPC genes separate into two types. One type holding 249 bp is identified exclusively in the K. pneumoniae isolates, whereas the other type with 248 bp and a slightly different nucleotide sequence is found only in K. oxytoca and S. enterica producing KPC-1 and KPC-2, respectively.
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The SME enzymes |
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The SME enzymes have been found exclusively in Serratia marcescens (S. marcescens enzyme) (Table 3) and the three variants differ by one to two amino acid substitutions. Geographically, SME-producing isolates have been collected in UK88 and infrequently and sporadically across USA (MA, IL, TX, OH, WA and CA).65,67,89,90
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The blaSME genes are seemingly not ubiquitous in S. marcescens, but the genes are more likely present in only a subpopulation of the species. The genes are presumed to be chromosomal and non-mobile, but no data have, however, been presented to document this assumption.
Among the S. marcescens isolates producing an SME enzyme, the blaSME-1 gene is so far the only one that is found associated with a gene encoding a regulator of the LysR type.93 Owing to the lack of sequence data, it is not known whether any of the other blaSME genes is linked to a LysR regulator gene. The upstream sequence (123 bp long) from the blaSME-3 gene92 is 100% identical to the equivalent sequence from the blaSME-1 gene which suggests that the blaSME-3 gene may have an upstream-located LysR encoding gene. The genetic environments of the blaSME genes have not been investigated and consequently it remains unknown whether the genes are parts of mobile elements.
Only S. marcescens strain S6 has been studied for induction of the SME-1 enzyme.93 Induction with imipenem resulted only in a marginal increase of activity against imipenem93 suggesting that SME-1 may be produced at a high basal level. This presumed high basal level of expression of the SME-1 enzyme may be mediated by the SmeR regulator operating as an activator of the blaSME-1 gene transcription in the absence of a ß-lactam inducer, but in the presence of an inducer, it acts more strongly.93 The inducible expression of the other SME enzymes in the remaining S. marcescens isolates has not been investigated.
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The IMI/NMC-A enzymes |
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The fourth group encompasses the IMI/NMC-A enzymes (imipenemase/non-metallocarbapenemase-A) which form two subgroups, IMI and NMC-A, respectively. The NMC-A enzyme deviates by eight amino acid substitutions from the two IMI variants which differ by two substitutions from each other. The enzymes have been found sporadically (Table 3), both in clinical isolates94,95,97–99 and in environmental isolates from rivers in USA.96
The clinical isolates carrying the chromosomal blaNMC-A gene all have an adjacent nmc-R gene.98–100 The NmcR regulator affects the transcription of its linked bla gene in the same manner as the SmeR regulator100 and AmpD has been found to be involved in the regulation of the Nmc-A carbapenemase.101
The blaIMI-1 gene and its linked imi-R gene coding for a LysR transcriptional regulator are embedded in the chromosome of the host,94 whereas the blaIMI-2 genes and their imi-R genes are plasmid-borne.95,96 The adjacent regions flanking the blaIMI-R–blaIMI-1 complex have not been analysed, but the complex may possibly be a part of a composite transposon.
The plasmid-borne imi-R–imi-2 gene complexes in Enterobacter cloacae and Enterobacter asburiae appear to be flanked by transposable elements.95,96 The blaIMI-R–blaIMI-2 region in E. asburiae is surrounded upstream by an IS2-like fragment and downstream by a transposase gene similar to the tnpA gene of Tn2501.96 The blaIMI-R–blaIMI-2 unit in E. cloacae is flanked on both sides by structures related to the tnpA gene of Tn903 and further upstream by an IS2-like element.95 Originally, these transposable elements may have been involved in mobilization of the blaIMI genes to the chromosome and to the plasmids, but whether they still are mobile is not known. If the transposable elements became inactive some time after the mobilization, it may explain the rare occurrence of the enzymes in these species.
Challenging of the IMI-producing isolates with imipenem results in substantial increases of activity against imipenem,94,96 whereas the IMI-2-producing E. cloacae showed a less strong induction.95 A high basal level of expression of IMI-2 because of mutational derepression may explain why the production of this enzyme is only marginally induced.95
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The SFC-1 and SHV-38 enzymes |
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Each of the last two groups contains a single enzyme, namely SFC-1 and SHV-38, from isolates of S. fonticola and K. pneumoniae, respectively. The S. fonticola strain was an environmental isolate from Portugal,102 whereas the K. pneumoniae isolate was recovered in France,103 and both enzymes are chromosomally encoded. The SFC-1 enzyme is not ubiquitous in S. fonticola because it is found only in this environmental isolate and not in other strains of S. fonticola.102 The SHV-38 enzymes differ by a single substitution from the broad-spectrum ß-lactamase, SHV-1.
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Origin of class A carbapenemases |
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The soil organism, Streptomyces cattleya, is a natural producer of the carbapenem compound, thienamycin,104,105 and imipenem is an N-formimidoyl derivative of thienamycin. Environmental microbiota carrying genes encoding for carbapenem-hydrolysing enzymes would thus be better endowed to survive in this environment.
The first identified isolate expressing a class A carbapenemase was the SME-1-producing S. marcescens from London.88 The isolate was recovered in 1982 before imipenem was approved for general use. Similarly, the E. cloacae isolate producing IMI-1 was collected in 1984 in USA.94 Likewise, a class D carbapenemase, OXA-23, was identified in an A. baumannii isolate which was recovered in 1985 in UK prior to launch of imipenem for clinical use.106
The imipenem-resistant phenotype in these instances preceded the clinical use of imipenem because the drug was first allowed for clinical use in 1985 in USA.1 These findings strongly suggest that the clinical use of imipenem has not been responsible for the evolution of the class A and D carbapenemases. The enzymes were probably present in bacteria long before, but the ancestors may have faded into the mists of history.
From the dendrogram in Figure 1, it appears that the IMI/NMC-A, SME, KPC and SFC-1 enzymes share a common origin which is quite distinct from the ancestors of the GES enzymes and SHV-38. The latter enzyme is the only class A carbapenemase with an identified ancestor.107 The intrinsic carbapenemase activity of all members of the IMI/NMC-A, SME, KPC and SFC-1 clusters suggests that the ancestral enzyme(s) may also have held the ability to hydrolyse carbapenems. It is also noticeable that the only clusters of class A carbapenemase genes associated with a LysR regulator gene are those most identical to each other, i.e. the blaIMI, blaNMC-A and blaSME genes, which appear to have descended from a common ancestor (Figure 1). The encoding genes are, however, far from ubiquitous in the species that carry them.
The cluster including the GES-type carbapenemases also encompasses ESBLs and a cephamycinase. The ability to hydrolyse carbapenems is evidently not an innate property of all GES enzymes, but instead some GES enzymes may have evolved the carbapenemase activity by amino acid substitutions. Thus, it cannot be excluded that the ancestral enzyme(s) of the GES cluster enzymes may have lacked the ability to hydrolyse carbapenems.
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Biochemical properties of class A carbapenemases |
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Mature class A carbapenemases are monomeric enzymes that contain between 265 and 269 amino acid residues with experimentally determined molecular masses that range from 25 to 32 kDa. The isoelectric points of the enzymes vary from 5.8 to 9.7.
Like other active-site serine ß-lactamases, class A carbapenemases also proceed via a simple three-step mechanism involving acylation and deacylation.6
Class A carbapenemases can phenotypically be divided into different subgroups of the group 2 ß-lactamases accordingly to the Bush–Jacoby–Medeiros classification scheme.36 As GES-1, GES-2 and SHV-38 hydrolyse the extended-spectrum cephalosporins, cefotaxime or ceftazidime, at a rate 10% than that for benzylpenicillin, the enzymes are assigned to subgroup 2be which encompasses the ESBLs. The SME, IMI and NMC-A enzymes are all assigned to the Bush subgroup 2f ß-lactamases, which are enzymes hydrolysing imipenem at a rate 200% than for benzylpenicillin.36
The kinetic data in Table 4 indicate that GES-4 and the KPC enzymes are better cephalosporinases than penicillinases, whereas the hydrolysis rates for extended-spectrum cephalosporins are lower than for penicillins. The KPC enzymes were originally assigned to the Bush subgroup 2f.63,70 The enzymes of subgroup 2f have relative rates of hydrolysis of imipenem that are 200% than of benzylpenicillin,36 whereas the analogous relative rates of the subgroup 2e enzymes are < 50% than of cephaloridine.36 The relative rates of hydrolysis of imipenem of GES-4 and the KPC enzymes are < 50% than of cefaloridine and < 200% than of benzylpenicillin. As the hydrolysis rates of other ß-lactams also correspond to those of subgroup 2e enzymes, it seems reasonable to categorize the GES-4 and KPC enzymes as subgroup 2e enzymes rather than subgroup 2f enzymes. This classification is also corroborated by the fact that the enzymes do not have high affinities for aztreonam (Table 4), and they are inhibited by clavulanate, although only weakly in comparison with the subgroup 2f enzymes. Table 4 also demonstrates that the relative rate of hydrolysis of imipenem of GES-5 is < 50% than of cefaloridine and < 200% than of benzylpenicillin, and besides, GES-5 seems to hydrolyse penicillin at a higher relative rate than classical and extended-spectrum cephalosporins. Thus, it is seems justified to classify GES-5 as a Bush subgroup 2br enzyme which includes broad-spectrum penicillinases inhibited by clavulanate.36
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As seen with OXA-type and zinc-dependent carbapenemases, the class A carbapenemases hydrolyse meropenem at a much lower rate than imipenem whereas their affinity for meropenem consistently is much higher (lower Km) than for imipenem (Table 4).
A multiple sequence alignment of the GES enzymes shows that enzymes displaying carbapenemase activity (GES-2, -4, -5 and -6) hold either a Ser or an Asn residue (GES-2) at position 170 (Ambler numbering),34 whereas the remaining GES enzymes all have a Gly residue. The residue at position 170 is located in the 
-loop which forms the bottom of the active site.48
The GES-6 enzyme confers reduced susceptibility to carbapenems in an E. coli transconjugant,49 but the in vitro kinetic parameters of GES-6 have not been determined. A disc diffusion bioassay showed, however, that GES-6 also has detectable carbapenemase activity like GES-5.49 Because GES-6 holds the same Gly-170 to Ser substitution as GES-5 it is conceivable that GES-6 may also possess measurable enzymatic activities against carbapenems.
The GES-4 enzyme which differs from GES-3 only by a Gly-170 to Ser substitution degrades not only carbapenems but also the cephamycin, cefoxitin (Table 4). This property is in contrast to the GES-3 enzyme which hydrolyses neither carbapenems nor cefoxitin to measurable extents.48 GES-5 holds the same Gly-170 to Ser substitution as GES-4 and also displays cephamycinase activity (Table 4). The GES-6 enzyme has detectable carbapenemase activity,49 but the MIC of the GES-6-producing E. coli transformant to cefoxitin has not been determined.
The GES family enzymes possess an unusual phenotypic plasticity, like the TEM and SHV enzymes, because the GES enzymes have activities against carbapenems, extended-spectrum ß-lactams, cephamycins or monobactam.
The difference between the broad-spectrum penicillinase, SHV-1 and SHV-38 is an Ala-146 to Val substitution (Ambler numbering)34 owing to a single transition. Among the available 78 different SHV enzymes in the GenBank database, only SHV-38 possesses Val in this position, all other SHV ß-lactamases have an Ala residue and none of these enzymes has carbapenemase activity. SHV-38 does not hydrolyse meropenem in measurable amounts.103
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Structure–function relationship |
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Class A ß-lactamases are folded into two globular domains, one entirely
-helical and the second with five ß-strands surrounded by -helices.110–112 The catalytic site with the active-site serine residue, Ser70, is located at the interface between the two domains. The B3 strand (residues 230–238) forms one wall of the active-site cavity while the bottom of this cavity consists of the so-called -loop encompassing residues 160–180.110 Other key residues involved in the formation of the active site are the canonical triads, S130DN and K234TG, together with the invariant Glu166 that acts as a general base. Despite only moderate amino acid sequence identities among the clusters of class A carbapenemases, the enzymes may share similar protein folds enabling them to hydrolyse carbapenems. Apart from SHV-38, all class A carbapenemases seem to contain a unique disulphide bridge between Cys69 and Cys238, and the bond appears to stabilize the protein fold.113 The S–S bond seems to be critical for the biological function of SME-1 as mutant enzymes without the bond do not confer resistance to ß-lactams.113,114 It is, however, not likely that the disulphide bond between these two residues in any class A ß-lactamase is a prerequisite for hydrolysis of carbapenems as an engineered S–S bond in the ESBL, Toho-1, results in a continually unmeasurable hydrolysis of imipenem.115 Therefore, it seems reasonable to assume that other structural features are required for hydrolysis of carbapenems. This is also consistent with the findings by Majiduddin and Palzkill116 that multiple residues may affect the conformation of the active-site cavity.
The crystal structures of SME-1, NMC-A and the SHV-38-related SHV-1 have been determined and the enzymes share an overall structural organization with other class A ß-lactamases.113,117,118
In contrast to other class A ß-lactamases, including the NMC-A enzyme, SME-1 lacks the catalytic water molecule that is generally positioned in the substrate-binding site between Ser70 and Glu166.113 This water molecule typically serves as the deacylating agent of the acylated enzyme, but instead, another water molecule situated in the oxyanion hole of SME-1 is hypothesized to serve as the catalytic water molecule.113
In SME-1, the His105 residue is positioned on one side of the active-site cleft where the residue is involved in binding of the antimicrobial compound.113 This residue is replaced by Tyr in SME-3 resulting in moderate changes of some in vitro kinetic parameters (Table 4), most noticeable for imipenem.
The Ser237 residue in SME-1 contributes significantly to catalytic activity against imipenem119 because the side chain of Ser237 is stabilized by formation of hydrogen bonds between the side chain and Arg220.113 Replacement of Ser237 with Ala whose side chain is not capable of forming hydrogen bonds results in a 5-fold reduction of kcat for imipenem.119
The crystal structure of the NMC-A enzyme described by Swarén et al.118 shows that the distance between the Ser70 and Glu166 residues is longer than in SME-1 which allows for accommodation of the typical catalytic water molecule.113 Compared with other class A ß-lactamases devoid of carbapenemase activity, shifts in positions of Asn132 in the conserved SDN motif and residues at positions 237–240 adjacent to the KTG triad in NMC-A have occurred.118
Among the GES enzymes, the Gly-170 to Ser substitution appears to be critical for carbapenemase activity, but it is unknown how this substitution affects the catalytic mechanism of the enzymes. It is possible that the side chain of the substituted Ser residue forms new hydrogen bonds in the active site which eventually may lead to carbapenem hydrolysis. However, this has to await the elucidation of the crystal structure of a GES carbapenemase which currently is underway.61
The SHV-38 enzyme differs from the broad-spectrum penicillinase, SHV-1, by an Ala-146 to Val substitution and in SHV-1 this residue is exposed to the solvent.117 Owing to the larger size and especially the more hydrophobic nature of the side chain of Val, this substitution may induce subtle structural perturbations in SHV-38 which may favour the insertion and hydrolysis of carbapenems in the active site of SHV-38. It is known from the IMP metallo-ß-lactamase that a substitution remotely located from the active-site has an improving effect on the catalytic efficiency towards imipenem.120
Apart from the disulphide bridge, no major structural differences have been recorded between class A carbapenemases and non-carbapenemases. Therefore, it is possible that interactions between specific residues lining the active-site pocket bring about the spatial and mechanistic basis for carbapenem hydrolysis.
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Conclusions |
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The number of different class A ß-lactamases with carbapenemase activity is still limited and the occurrence of most class A carbapenemases is at present sporadic. The most widely dispersed enzymes, the GES and KPC enzymes, are encoded by genes located on transferable elements facilitating their dissemination which is also reflected in the geographical distribution of the GES and KPC enzymes. The KPC carbapenemases have established themselves especially in K. pneumoniae recovered from the Northeastern parts of USA, but the enzymes have also been recorded outside USA. In the light of the rapid spread of the CTX-M enzymes and the plasmid-borne AmpC ß-lactamases, it is conceivable that a similar scenario may occur for the GES and KPC carbapenemases. Carbapenems are often used to combat severe infections caused by multiresistant pathogens because the drugs resist hydrolysis by most ß-lactamases, including ESBLs and derepressed chromosomal AmpC ß-lactamases. A wider dissemination of the GES and KPC carbapenemases would therefore pose therapeutic problems as the options for treatment may be restricted, possibly with fatal consequences.
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Transparency declarations |
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None to declare.
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