Division of Microbiology, School of Biochemistry and Molecular Biology, and the Antimicrobial Research Centre, University of Leeds, Leeds LS2 9JT, UK
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Abstract |
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Introduction |
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The introduction of the semi-synthetic penicillins and the early cephalosporins in the 1960s broadened the spectrum of activity of ß-lactams. These newer drugs could be used to treat Gram-negative infections, including life-threatening conditions. As with the staphylococci, however, the problem of ß-lactam resistance rapidly emerged in Gram-negative bacteria. In clinically significant bacteria, resistance to ß-lactams was due to the production of ß-lactamases and amongst the most important of these were the TEM and SHV enzymes.2,3
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Classification of ß-lactamases |
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As with classification schemes, there has also been considerable confusion over the nomenclature of ß-lactamases. There is no rational basis for the naming of these enzymes. The name `TEM' is a contraction of Temoniera, the name of a patient from whom resistant bacteria were isolated. In contrast, `SHV' is a contraction of sulphydryl variable: a description of the biochemical properties of this ß-lactamase. Furthermore, ß-lactamases may be given one name when first identified, only to have this name changed after subsequent studies have allowed a more complete characterization of its properties. CTX-1 was so called because it conferred resistance to cefotaxime. Nucleotide sequence analysis showed that this enzyme had arisen by the accumulation of point mutations in the gene encoding a TEM ß-lactamase. Consequently, CTX-1 is now named TEM-3. Similarly, SHV-1 has also been called PIT-2: it was first described by Pitton in 1972.16 Such confusion is typical of studies of ß-lactamases and can lead to problems when reviewing literature in this area.
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Spread of genes conferring resistance to ß-lactam antibiotics |
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The narrow-spectrum ß-lactamases related to SHV-1 |
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The enzyme kinetics and biochemical profiles of OHIO-1, LEN-1 and SHV-1 are very similar and resemble those of TEM-1.1 None of these enzymes is able to hydrolyse extended-spectrum cephalosporins, cephamycins, monobactams or carbapenems. They can, however, inactivate the narrow-spectrum cephalosporins such as cefamandole and cefoperazone and are active against penicillins. Bacteria producing SHV-1 and LEN-1 are distributed globally; OHIO-1 is, at present, restricted to bacteria isolated in the American state of Ohio.
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The introduction of extended-spectrum cephalosporins and the emergence of associated extended-spectrum ß-lactamases |
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By the mid-1980s, resistance to extended-spectrum cephalosporins had appeared in clinically significant Gram-negative bacteria. The basis of this resistance was production of ß-lactamase.21,22,23 Among the first of the extended-spectrum ß-lactamases to cause significant clinical problems were mutants derived from the narrow-spectrum SHV-1 or TEM-1 ß-lactamases. The genes encoding these mutants are present on mobile genetic elements, facilitating their spread in nosocomial pathogens.1
The first extended-spectrum SHV enzyme was described in 1983 in clinical isolates of K. pneumoniae, Klebsiella ozaenae and Serratia marcescens.21 Because of its similarity to SHV-1 the new enzyme was named SHV-2.24 A single amino acid substitution alters the spectrum of activity of the SHV-1 ß-lactamase to encompass extended-spectrum cephalosporins. Glycine at position 238 in SHV-1 is replaced by serine in SHV-2.25
In 1988, Jarlier et al.22 described SHV-3, a ß-lactamase isolated from K. pneumoniae. This was isolated from a patient in an intensive therapy unit in a French hospital where SHV-2 had also been reported. Both SHV-2 and SHV-3 have a spectrum of activity that includes extended-spectrum cephalosporins and they share a substrate and inhibitor profile. At the nucleotide sequence level, a point mutation causes the substitution of leucine at amino acid position 205 in SHV-3 for the arginine that is found at that position in both SHV-1 and SHV-2. SHV-3 also has a serine residue at amino acid position 238. It is thus probable that it evolved from SHV-2 by a point mutation. This mutation significantly alters the isoelectric point of the enzyme. The isoelectric point of both SHV-1 and SHV-2 is 7.6, whereas that of SHV-3 is 7.0.
Soon after the first description of SHV-3, yet another member of this family was described.26 The SHV-4 ß-lactamase is another enzyme with extended-spectrum cephalosporinase activity. It was first described from K. pneumoniae and, like SHV-3, it was first seen in a French hospital. Strains of K. pneumoniae that elaborate SHV-4 disseminated rapidly and by 1990 they had been found in 14 hospitals throughout France.27 The isoelectric point of SHV-4 is 7.8. Analysis of amino acid sequence data shows that SHV-4 evolved by a point mutation in the gene that codes for SHV-3. In the case of SHV-4 the amino acid substitution occurs at position 240, where lysine replaces the glutamic acid found in this position in the other members of the SHV family.
The fifth member of the SHV family was first observed in Chile.28 This was the first variant not to have been first observed in Europe. SHV-5 was again first described from K. pneumoniae and has an isoelectric point of 8.2. As with SHV-4, the amino acid found at position 240 in SHV-5 is lysine. It is impossible, however, to say from which ancestral gene the SHV-5 determinant evolved: it may have evolved by point mutation from either SHV-4 or SHV-2.
The SHV-6 ß-lactamase was discovered in 1991.29 This is an unusual enzyme in that its spectrum of activity is different from other extended-spectrum ß-lactamases in this family. SHV-6 can hydrolyse ceftazidime but it has no activity against other extended-spectrum cephalosporins such as cefotaxime. It is also inactive against monobactams such as aztreonam, which distinguishes it from other extended-spectrum SHV enzymes. It was first found in France where it was produced by a strain of K. pneumoniae isolated from a patient on a paediatric oncology ward. It is probable that SHV-6 arose by point mutation from SHV-1 since these two enzymes differ only at amino acid position 179 where the aspartic acid found in SHV-1 has been replaced with alanine in SHV-6.30 The isoelectric point of SHV-6 at 7.6 is indistinguishable from that of SHV-2, illustrating the difficulties of using this as a method of characterizing ß-lactamases. This also demonstrates the importance of a rapid and reliable method of differentiating members of this family of enzymes.
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SHV-type extended-spectrum ß-lactamases do not only occur in Klebsiella pneumoniae |
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E. coli provided the background for the emergence of SHV-8.32 This was also first observed in the USA. It differs from SHV-1 by the substitution of asparagine in SHV-8 for the aspartic acid seen in SHV-1 at position 179. It is of considerable interest to note that SHV-1 has a relatively narrow spectrum of activity, whereas SHV-8 has significant activity against extended-spectrum cephalosporins and monobactams. SHV-6 also differs from SHV-1 by a single amino acid at this position. In the case of SHV-6, the amino acid is alanine. This substitution has a profound effect upon the activity of this enzyme. It is also of interest that although these mutations affect the spectrum of activity of these three enzymes, they all share the same isoelectric point (7.6).
The SHV-9 ß-lactamase33 appears to have evolved from SHV-5 in another two-step process. This enzyme was found to be produced by E. coli, K. pneumoniae and S. marcescens isolated from a Greek Hospital in 1995. It differs from SHV-5 by the substitution of arginine for alanine at position 140. There is also a triplet deletion causing the loss of amino acid 54 from SHV-9. Again, the double change implies that there is another SHV enzyme awaiting discovery. The first inhibitor-resistant SHV ß-lactamase, SHV-10, was first seen produced by E. coli. It is derived from SHV-9 by a single amino acid substitution at position 130.34 The serine that is typically found in this position has been changed to glycine in SHV-10. Both SHV-9 and SHV-10 have isoelectric points of 8.2.
The latest additions to the SHV family were both first described from Switzerland and are found in a number of species in the Enterobacteriaceae family.35 SHV-11 is a variant of either SHV-1 or SHV-3 and it does not possess extended-spectrum cephalosporinase activity. It has a glutamine instead of leucine at amino acid 35. SHV-12, an extended-spectrum ß-lactamase, also has glutamine at position 35 and it probably evolved by a point mutation from SHV-5. To complete the current evolutionary picture (Figures 1 and 2), either the gene encoding SHV-2 or that encoding SHV-12 has undergone a point mutation to yield SHV-2a.36 The first report of each of the SHV ß-lactamases are summarized in Table I.
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The structurefunction relationship in SHV ß-lactamases |
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Substitutions at other positions increase hydrolytic activity against ceftazidime and aztreonam. The substitution of lysine at position 240 replaces a strongly negatively charged amino acid, glutamic acid, at the bottom of the ß-pleated sheet. This attracts and binds the terminal carboxyl group on the long oxyamino side chain of these two agents.64 This substitution is seen in SHV-4, SHV-5 and SHV-7. The first two of these enzymes are now frequently encountered, perhaps reflecting the selective pressure of increased usage of ceftazidime. Substitution of lysine for glutamic acid at position 240 is also seen in SHV-9, SHV-10 and SHV-12, all related to SHV-5. Mutations at position 205 seen in SHV-3 and SHV-4 are located on a helix that lies adjacent to the serine at position 70 in the active site. The precise mechanism by which these alterations contribute to extended-spectrum ß-lactamase activity is not yet clear.65
There have been predictions that inhibitor-resistant extended-spectrum ß-lactamases might arise by selection of SHV ß-lactamases. It has been proposed that they could acquire a mutation at position 69 where methionine is substituted by isoleucine. Similar alterations have been described in a laboratory mutant of OHIO-1.66 Mutants of SHV-5 carrying substitutions of isoleucine or valine at position 69 have been constructed.67 Although resistant to inhibitors such as clavulanate, these mutants display a very marked reduction in resistance to penicillins and cephalosporins with the MICs of cefotaxime, ceftazidime and aztreonam being 2 mg/L, 816 mg/L and 8 mg/L, respectively. Alteration at position 69 will affect the positioning of adjacent amino acids and the loss of activity may be due to displacement of the serine at position 70. This is important for binding the ß-lactam to the active site of the enzyme. Thus, alterations at position 69 may move the adjacent serine away from the substrate.65 Interestingly, the first inhibitor-resistant SHV ß-lactamase to arise by natural selection, SHV-10, carries a mutation at position 13034 rather than at amino acid 69. This illustrates the danger of predicting the course of the natural evolution of genes based upon experiments performed under laboratory conditions. The amino acid substitutions and isoelectric point of each SHV ß-lactamase are summarized in Table II.
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Evolutionary relationships and spread of genes encoding the SHV family of ß-lactamases |
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It is of interest to note that the early members of the SHV family were all first described in strains of K. pneumoniae. Later, E. coli was also the host for variants in this family. The genes encoding these ß-lactamases are, however, frequently found on self-transmissible plasmids. They have now been found in other members of the Enterobacteriaceae including important nosocomial pathogens such as Citrobacter diversus, Klebsiella oxytoca and Morganella morganii. They have also been reported to be produced by P. aeruginosa76 and Burkholderia cepacia.60 These genes have been mobilized to a wide range of Gram-negative pathogens.
There has also been considerable geographical spread of these ß-lactamases. Although SHV-2 was first described in Germany21 it, and its variant SHV-2a, has since been seen around the world. Like SHV-2, its variant, SHV-2a, first appeared in Germany.46 These enzymes have subsequently been found in the USA and are particularly common in countries that border the Mediterranean where they often occur in salmonella isolates.39 The SHV-5 ß-lactamase shows a similar widespread geographical distribution.77 In contrast to SHV-2 and SHV-5, bacteria producing SHV-3 and SHV-4 have been found to be more geographically restricted: they have both only been reported from France.27,78 Bacteria producing SHV-4 have, however, been responsible for infections in 14 separate hospitals. This ß-lactamase has been found in C. diversus as well as K. pneumoniae.79 It would thus appear to be able to spread with relative ease. Further reports of bacteria that produce this ß-lactamase are awaited from elsewhere in the world. Other ß-lactamases of the SHV family tend to occur sporadically. The appearance of variants of the SHV ß-lactamase in various geographical locations implies co-evolution of these genes, mirroring the convergent evolution described for members of the blaTEM family.80 The data on geographical distribution of SHV ß-lactamases are summarized in Table I.
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Methods used to characterize members of the SHV family of ß-lactamase |
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Biochemical analyses lack discrimination and the determination of isoelectric points is technically demanding and prone to error. Full nucleotide sequence determination provides a definitive identification but this is beyond the scope of a routine diagnostic practice. Consequently, we have developed an identification technique based upon PCR and Single Strand Conformational Polymorphism, (PCRSSCP).82
A very short PCR amplimer is generated and the DNA strands are separated and subjected to electrophoretic analysis. Single point mutations alter the conformation of the denatured strands, thus altering the electrophoretic mobility of short products. The precise nature of these changes depends upon the position and nature of the mutation. We have successfully applied PCRSSCP to the identification of SHVß-lactamase genes up to blaSHV-783 and have used it in cases where resistance to ß-lactam antibiotics is mediated by more than one class of ß-lactamase.84 The success of this method with the blaSHV-7 gene is significant. The functional mutations that are responsible for the amino acid substitutions in this enzyme fall outside the target for the PCR amplification used in subsequent SSCP analysis. We can successfully apply this technique to the characterization of blaSHV-7 because the gene carries silent mutations that occur within the amplified target DNA. Other blaSHV genes that carry silent mutations within the amplimer target will thus, by extrapolation, be identified using PCRSSCP. This technique can also be applied to strains that harbour more than one blaSHV gene.83 In such cases, the two predicted SSCP patterns appear superimposed upon one another. The SSCP technique can be used to provide a rapid and reliable characterization of point mutations in any short DNA sequence. It can thus be applied to the characterization of other resistance determinants where point mutations have a role in the expression of a resistance phenotype. This may include the genes encoding other ß-lactamases or, indeed, resistance to other antimicrobials.
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Conclusions |
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Acknowledgments |
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Notes |
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References |
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Received 12 August 1998; returned 2 November 1998; revised 16 March 1999; accepted 26 May 1999