Journal of Antimicrobial Chemotherapy

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Journal of Antimicrobial Chemotherapy (1999) 43, 447-458
© 1999 The British Society for Antimicrobial Chemotherapy

Review

Inhibitor-resistant TEM ß-lactamases: phenotypic, genetic and biochemical characteristics

E. B. Chaïbi^a, D. Sirot^b, G. Paul^c and R. Labia^a,*

^a UMR 175, CNRS-MNHN, 6 Rue de l'Université, 29000 Quimper ^b Laboratoire de Bactériologie, Faculté de Médecine, 28 Place Henri-Dunant, 63001 Clermont-Ferrand Cedex ^c CHU Cochin, Laboratoire de Bactériologie, 75014 Paris, France

	Abstract

Top Abstract Introduction Phenotypic characteristics Genetic characteristics Biochemical data Relationship between structure... Conclusions References

 
ß-Lactamases represent the main mechanism of bacterial resistance to ß-lactam antibiotics. The recent emergence of bacterial strains producing inhibitor-resistant TEM (IRT) enzymes could be related to the frequent use of ß-lactamase inhibitors such as clavulanic acid, sulbactam and tazobactam in hospitals and in general practice. The IRT ß-lactamases differ from the parental enzymes TEM-1 or TEM-2 by one, two or three amino acid substitutions at different locations. This paper reviews the phenotypic, genetic and biochemical characteristics of IRT ß-lactamases in an attempt to shed light on the pressures that have contributed to their emergence.

	Introduction

Top Abstract Introduction Phenotypic characteristics Genetic characteristics Biochemical data Relationship between structure... Conclusions References

 
Increased and repeated use of ß-lactam antibiotics (e.g. penicillins and cephalosporins) leads to them becoming ineffective, principally as a result of the onset and world-wide spread of enzymatic resistance via ß-lactamase production by bacteria. Two strategies have been employed to counter this resistance problem. Firstly, new ß-lactam drugs have been developed that are inherently less susceptible to ß-lactamases. A second approach utilizing combinations of a mechanism-based inactivator for ß-lactamases (e.g. clavulanic acid, sulbactam and tazobactam) and a penicillin has also been used. The rationale for such combined therapy is based on a synergic effect of the two molecules: the inactivator destroys the ß-lactamase activity, whereby the penicillin is protected from inactivation. Combinations of hydrolysable penicillins with a ß-lactamase inhibitor are a successful strategy to overcome TEM-type mediated resistance. Reports have established that the susceptibility of Escherichia coli isolates to ß-lactamase inhibitors can be affected by hyperproduction of unmodified TEM-type ß-lactamase,^1,2,3 or by the modification of the outer membrane proteins, or by both.⁴ Resistance may also be attributable to production of OXA-type enzymes, or to hyperproduction of cephalosporinases.⁵ Since 1990, the effect of ß-lactamase inhibitors has also been compromised by the emergence of mutant TEM-type ß-lactamases,^6,7 collectively designated inhibitor-resistant TEM or IRT ß-lactamases (Table I).

View this table: [in this window] [in a new window]   Table I. Amino acid substitutions in the IRT ß-lactamases

 
Until now, the IRT ß-lactamases have been described only in Europe (France,^{7,8,9,10,11,12,13,14,15} Spain¹⁶ and the UK^6,17). It is probable that bacterial strains producing IRT enzymes are also widespread on other continents, but the lack of reports may result from inadequate techniques for detection of the IRT phenotype. The production of IRT has been detected only in strains of Enterobacteriacae, particularly in E. coli, but also in three clinical strains of Klebsiella pneumoniae^18,19 and ten strains of Proteus mirabilis.¹² The presence of IRT was also reported in 1993 in strains of E. coli and of Citrobacter freundii, isolated from calf faeces.²⁰ IRT enzymes have never been observed in Haemophilus influenzae although co-amoxiclav is widely prescribed to treat infections caused by ß-lactamase-producing strains of this bacterium. As suggested by Nicolas-Chanoine,²¹ this could be related to a high intrinsic activity of penicillins against such strains or to an inadequate number of bacteria in the natural reservoir (the oropharynx) to allow for the spontaneous point mutation of the plasmidic TEM gene. Moreover, this species makes only a small amount of ß-lactamase.

This review attempts to summarize and to discuss the many available data concerning the IRT ß-lactamases.

	Phenotypic characteristics

Top Abstract Introduction Phenotypic characteristics Genetic characteristics Biochemical data Relationship between structure... Conclusions References

 
Detection of IRT-producing strains

The IRT phenotype was characterized by resistance to ß-lactam-clavulanate combinations with susceptibility to cephalosporins, which is not observed in the overproduced penicillinase phenotype. A number of studies have tried to determine the resistance pattern which allows a reliable detection of IRT-producing strains.^22,23,24,25 When susceptibilities to amoxycillin, amoxycillin plus clavulanate, ticarcillin, ticarcillin plus clavulanate, piperacillin, piperacillin plus tazobactam and cephalothin were evaluated by a disc diffusion method with the critical diameters interpreted according to French guidelines,²⁶ the phenotype amoxycillin-resistant, ticarcillin-resistant, amoxycillin or ticarcillin plus clavulanate-intermediate or -resistant and cephalothin-susceptible allowed the detection of about 87% of E. coli strains producing an IRT ß-lactamase alone or in association with a parental TEM ß-lactamase.²⁴ However, this phenotype did not allow the discrimination of OXA-producing strains, which appeared indistinguishable from IRT strains (Table II). Libert et al.²⁷ proposed the measurement of the inhibition diameters to cefepime, mecillinam and ceftazidime for the routine differentiation of strains producing IRT and OXA enzymes.

View this table: [in this window] [in a new window]   Table II. ß-Lactam resistance phenotypes of amoxycillin–clavulanate-intermediate (I) and -resistant (R) E. coli strainsa

 
In a study using an automated and rapid (4–5 h) ATB method (bioMérieux, La Balme-les-Grottes, France) linked to a knowledge-based expert system (ATB Plus System, Golo V.1.5, bioMérieux) detecting `IRT' on the basis of growth indices obtained with ß-lactams, it was demonstrated that this system was able to detect 86.7% of IRT-producing E. coli strains.²⁸ By routine susceptibility tests, IRT production was inconstantly detected when it was present with additional ß-lactamases such as AmpC cephalosporinase.²⁴

ß-Lactam susceptibility of IRT-producing E. coli strains

The susceptibility of 98 IRT-producing isolates of E. coli, collected in 1993 in the teaching hospital of Clermont Ferrand (France), was assessed by determination of ß-lactam MICs by the agar dilution method (Table III). The isolates selected produced nine different IRT enzymes: TEM-30/IRT-2 (n = 19), TEM-32/IRT-3 (n = 4), TEM-33/IRT-5 (n = 16), TEM-34/IRT-6 (n = 13), TEM-35/IRT-4 (n = 13), TEM-36/IRT-7 (n = 11) TEM-37/IRT-8 (n = 19), TEM-38/IRT-9 (n = 1), and TEM-39/IRT-10 (n = 2).

View this table: [in this window] [in a new window]   Table III. Distribution of ß-lactam MICs (mg/L) for 98 IRT-producing E. coli isolates

 
For all the IRT-producing isolates high-level resistance to amoxycillin and ticarcillin (90% inhibitory concentration 4096 mg/L) was observed. Addition of clavulanic acid (2 mg/L) reduced the MICs of amoxycillin and ticarcillin only by two dilutions, this reduction being insufficient to render any of the isolates susceptible to these combinations. A lower degree of resistance to piperacillin than to amoxycillin and ticarcillin was observed for all IRT-producing isolates. These isolates had intermediate susceptibility to piperacillin (8 < MIC 64 mg/L) and only 39% of isolates were resistant (MIC > 64 mg/L). Addition of tazo bactam (4 mg/L) reduced substantially the piper a cillin MIC, as 84% of isolates were classified as susceptible to a piperacillin–tazobactam combination (MIC 8 mg/L). This could be due to the greater inherent activity of piper a cillin alone against IRT-producing isolates. In general, no particular differences were observed among MIC values obtained for isolates producing the various IRT types.

It is noteworthy that the piperacillin–tazobactam combination showed the best bacteriostatic effect against the isolates producing IRT enzymes. However, the cidal effect of this combination was not obtained (1% of survivors at 6 h) with concentrations of 1 x MIC, 2 x MIC, and 4 x MIC of piperacillin with tazobactam (4 mg/L), and regrowth was observed at 24 h (data not shown).

	Genetic characteristics

Top Abstract Introduction Phenotypic characteristics Genetic characteristics Biochemical data Relationship between structure... Conclusions References

 
Three bla gene sequences designated TEM-1A, TEM-1B and TEM-2 encode two different ß-lactamases, namely TEM-1 and TEM-2 (Table IV). There are a total of nine nucleotide sequence differences between these genes at positions 32, 175, 226, 317, 346, 436, 604, 682 and 925 (numbering according to Sutcliffe²⁹). Caniça et al.¹³ have explored the molecular diversity of IRT enzymes by using a strategy which involved DNA amplification by polymerase chain reaction (PCR), analysis of restriction fragment length polymorphism (RFLP) and direct nucleotide sequencing. Study of the primary structure of the genes encoding these enzymes with altered phenotype is expected to provide insight into the molecular basis of the phenotype and to help in tracing their evolution.Table V shows that the IRT ß-lactamase genes can be grouped in three sequence linkage groups: `TEM-1A like' `TEM-1B like' and `TEM-2 like'. It should be noted that a given mutation conferring an IRT phenotype can be found in two different gene frameworks: e.g. TEM-30/IRT-2, TEM-31/IRT-1 and TEM-34/IRT-6 are found independently in both `TEM-1B like' and `TEM-2 like' gene sequences. As suggested by Caniça et al.<sup>13</sup> these mutations can be considered as either recurrent (and hence at hot spots for mutations), or much more ancient than others, allowing their occurrence on two different gene matrices. Contrasting with this situation, ß-lactamases other than IRT-1, IRT-2 and IRT-6 are associated only with one of the sequence linkage groups, `TEM-1A like', `TEM-1B like' or `TEM-2 like'.

View this table: [in this window] [in a new window]   Table IV. Sequence differences between blaTEM-1A, blaTEM-1B and blaTEM-2 genes

 

View this table: [in this window] [in a new window]   Table V. Isolated or associated amino acid substitutions present in the IRT ß-lactamases; distribution among sequence linkage groups

 
It is significant to note that the IRT ß-lactamases can be hyperproduced by mutation at the level of their promoter genes. Indeed, Caniça et al.¹³ have described two nucleotide substitutions in the promoter region of the bla_IRT genes: C32RT and G162RT. The first substitution, C32RT, characteristic of the gene promoter of TEM-2,³⁰ was found in the promoter region of the TEM-1 gene of 15 clinical isolates of E. coli.³ The second substitution, G162RT, was found in the ß-lactamase genes of TEM-30/IRT-2, TEM-35/IRT-4, TEM-34/IRT-6, TEM-36/IRT-7, TEM-37/IRT-8, TEM-39/IRT-10 and TEM-45/IRT-14.¹³,¹⁵ This G162RT transversion falls within the functional 210 Pribnow box and consequently renders the 210 consensus region of the IRT ß-lactamase genes more similar to the optimal promoter of E. coli 59-TATAAT-39.³¹ The G162RT transversion has been also described as the mechanism of TEM-1 hyperproduction in two ampicillin–sulbactam-resistant Shigella flexneri isolates from Hong Kong.³²

These data are clear evidence for the convergent evolution of IRT enzymes because mutations have occurred independently on different gene frameworks (ancestor sequence), but all confer an identical IRT phenotype in response to selective pressure imposed by the clinical use of ß-lactamase inhibitors.¹³

	Biochemical data

Top Abstract Introduction Phenotypic characteristics Genetic characteristics Biochemical data Relationship between structure... Conclusions References

 
Kinetic parameters

Kinetic parameters (k_cat and K_m) and catalytic efficiency (k_cat/K_m) of TEM-1 and IRTs are shown in Table VI. Generally, most IRT ß-lactamases have lower catalytic efficiency values for all substrates than those of TEM-1. This results from a decrease of k_cat values and an increase of K_m values. The mutants which have one amino acid substitution at position 69 show catalytic efficiency values higher than those of other IRT mutants. This indicates the important contribution of residues 244, 275 and 276 in the enzyme–substrate interaction. It is noteworthy that all IRTs have high K_m values for ticarcillin (a carboxypenicillin). Similar results are obtained with carbenicillin, another carboxypenicillin (data not shown). For all IRTs this characteristic may be related to electrostatic interactions, as they have low K_m values for carfecillin (a phenyl ester of carbenicillin) (data not shown). The structures of ticarcillin, carbenicillin and carfecillin are shown inFigure 1. For the mutants at position 69, modelling suggests repulsion between the carboxylate of the side chain of ticarcillin (or carbenicillin) and a carboxylate of side chains of Glu-104 and Glu-240.³³ Other residue(s) required for these electrostatic interactions are still to be found.

View this table: [in this window] [in a new window]   Table VI. Kinetic data of TEM-1 and IRT ß-lactamases

 

View larger version (12K): [in this window] [in a new window]   Figure 1. Structures of some substrates and ß-lactamase inhibitors.

 
Interaction with clavulanic acid, sulbactam and tazobactam

The structures of ß-lactamase inhibitors are shown inFigure 1. All the IRTs have IC₅₀ and K_i values for ß-lactamase inhibitors higher than those of TEM-1 (Table VII). Those with mutations at position 69 exhibit lower IC₅₀ and K_i values than those of other mutants. Sulbactam is a poor inhibitor of all the IRT ß-lactamases (high IC₅₀ and K_i values), whereas tazobactam was the most active inhibitor (low IC₅₀ and K_i values), except against those mutations at position 69, indicating a more favourable interaction with the triazole ring-substituted penicillanic acid sulphone than with the naked sulphone. This finding is consistent with work published recently by Bonomo et al.³⁴ This study complements and extends previous investigations in which clavulanic acid and tazobactam have been shown to be more effective ß-lactamase inhibitors than sulbactam against extended-spectrum and conventional-spectrum enzymes and that clavulanic acid had activities equivalent to those of tazobactam.^35,36

View this table: [in this window] [in a new window]   Table VII. IC50 and Ki values of ß-lactamase inhibitors

 

	Relationship between structure and function

Top Abstract Introduction Phenotypic characteristics Genetic characteristics Biochemical data Relationship between structure... Conclusions References

 
In the absence of crystal structures, most structure–function relationships of the IRT ß-lactamases have been studied by molecular modelling. Two excellent reviews have recently discussed these relationships.^37,38Figure 2 shows the ribbon representation of the three-dimensional structure of a class A TEM-type ß-lactamase, established at the atomic level by X-ray crystallography,^39,40 together with the location of each of the point mutations. All the IRT variants arise from point mutations in the gene encoding either TEM-1 or TEM-2. At amino acid position 39, located at the end of the N-terminal -2 helix, TEM-1 enzymes have a glutamine and TEM-2 a lysine. The catalytic properties of these parental enzymes are slightly, but significantly, different.^41,42

View larger version (35K): [in this window] [in a new window]   Figure 2. Ribbon representation of a class A TEM-type ß-lactamase. In the ß-lactam binding site, the reactive Ser-70 is located at the N-terminus of the -2 helix.3940

 
Residue 69

Residue 69 is rather variable in size and character among class A ß-lactamases but is always in high conformational energy.^39,40,43,44 The importance of this amino acid is not its closeness to the reactive Ser-70, but rather the position of its side chain behind the ß-3 and ß-4 strands. It is adjacent to the oxyanion binding pocket formed by the amides of Ser-70 and Ala-237. The molecular modelling showed that the methyl of Val-69 (C1) and Ile-69 (C2) produced steric constraints with the side chain of Ser-70 and Asn-170.³³ The hydrophobicity could be the main factor responsible for the kinetic properties of the variant Met-69Leu (TEM-33/IRT-5), as no steric effects could be detected by molecular modelling.³³ Thus, hydrophobicity and steric constraints could be combined in the variants Met-69Val (TEM-34/IRT-6) and Met-69Ile (TEM-40/IRT-11). In addition, we speculate that residue 69 could interfere with the guanidinium group of Arg-244, as previously suggested for the Met-69Ile mutant of the SHV-type OHIO-1 ß-lactamase.⁴⁵

Residue 165

Located at the beginning of the -loop (position 161 to 179), the side chain of this residue is solvent-oriented. A change of Trp-165Arg is found in the TEM-39/IRT-10 ß-lactamase, but associated with two other substitutions at positions 69 and 276. The TEM-type variant Trp-165Arg made by site-directed mutagenesis exhibited a slight decrease to the inhibitory effect of clavulanic acid.⁴⁶ Molecular modelling suggests that the side chain of Arg-165 is able to form a salt bond with the -loop Glu-168 (unpublished data).

Residue 182

Located just before the -8 helix (position 183 to 195), this residue is rather far from the binding site. A threonine is present in the TEM-32/IRT-3 ß-lactamase. However, the enzyme contains a second change at position 69 that was shown to be the dominant factor in the resistance to ß-lactamase inhibitors.¹⁶ Molecular modelling showed a novel hydrogen bond between the hydroxyl of Thr-182 and the carbonyl of the amide bond of Glu-64.⁴⁷ That strengthens the dense hydrogen bond network that stabilizes the active site, and therefore was expected to be responsible for the increase in the catalytic activity of the TEM-32/IRT-3 ß-lactamase compared with that of TEM-40/IRT-11. Moreover, Huang & Palzkill⁴⁸ have recently demonstrated that the addition of the Met-182Thr substitution to the TEM-1 variant Met-69RIle increased the stability of the Met-69Ile enzyme. The Met-182Thr substitution may have been selected in natural isolates as a suppressor of folding or stability defects resulting from mutations associated with drug resistance.⁴⁸ It is noteworthy that with the sequences of 28 class A ß-lactamases previously aligned, TEM-1 was the sole protein exhibiting a Met at position 182, a position that generally has hydrogen bond-forming residues such as threonine, serine or cysteine.⁴⁹

Residue 244

Arg-244 is a relatively conserved residue on the ß-4 strand of class A ß-lactamases, but when absent a basic residue (Arg or Lys) is found at position 220 or at position 276.^38,49,50 It is anchored in place by two hydrogen bonds to Asn-276. Via a well-ordered, structurally conserved water molecule, it may interact with the C-3 (C-4) carboxylic acid group of ß-lactams.^51,52,53,54 However, Delaire et al.⁵⁵ believe there are no direct interactions with the acid group and that the role of Arg-244 is to destabilize the enzyme product complex and optimize the turnover rate.

When Arg-244 is replaced by an amino acid with a short side chain such as cysteine, serine or histidine, the enzyme–substrate interaction is modified and affinity for the substrate decreases (Table VI). Moreover, the shorter side chains of these residues would be unable to activate the water molecule involved in the inactivation process of clavulanate.⁵¹ Sulbactam and tazobactam are thought to use a different mechanism and are not dependent on the structurally conserved water molecule.⁵⁶ An unexpected finding that the doubly mutated derivative of the TEM-1 enzyme (Ser-164/Ser-244) retains the characteristics of the Ser-164 mutant enzyme, e.g. enhanced activity against ceftazidime and sensitivity to inactivation by clavulanate, is perhaps due in part to structural changes resulting from the disruption of the -loop.⁵⁷ Arg-244 or a water molecule co ordinated to its side chain also plays an essential role in the carbapenem tautomerization in the ß-lactamase TEM-1 active site.^58,59

Residue 261

Located at the ß-5 strand, its side chain is buried at the hydrophobic region far from the active site. The amino acid substitution Val-261Ile is found in TEM-58,¹⁵ but is associated with the change Arg-244Ser which is involved in the resistance of TEM-30/IRT-2 to ß-lactamase inhibitors.

Residue 275

Located at the C-terminal of the -11 helix, its side chain is in close vicinity to the guanidinium group of Arg-244. Substitution of Arg-275 by leucine or glutamine is found in the ß-lactamases TEM-38/IRT-9 and TEM-45/IRT-14, respectively. However, these enzymes contain a second change at position 69 (Val or Leu). Kinetic study of the Arg-275Leu variant of the TEM-type ß-lactamase has shown the involvement of this change in the resistance to inactivation by clavulanic acid.⁶⁰ This could be related to electrostatic interactions with Arg-244 and/or to a possible displacement of the water molecule involved in the inactivation.

Residue 276

The partially exposed side chain at residue 276 is on the C-terminal -11 helix. In the TEM-1 ß-lactamase the carbonyl group of Asn-276 accepts two hydrogen bonds from Arg-244 that orient the guanidinium group. The amino acid substitution Asn-276Asp is found in the natural variants TEM-35/IRT-4, TEM-37/IRT-8 and TEM-39/IRT-10, but associated with another change at position 69. Brun et al.,¹⁰ by comparing the kinetic properties of the TEM-35/IRT-4 enzyme and the Met-69Leu variant of the TEM-type enzyme, have suggested a direct or an indirect role of Asp-276 in the catalytic mechanism. Thus, the TEM-type variant Asn-276Asp made by site-directed mutagenesis exhibited decreased affinity and catalytic efficiency for ß-lactam substrates, as well as a 20-fold higher K_i for clavulanate.⁶¹ The resistance to the inactivation process of clavulanic acid could be linked to electrostatic interactions with Arg-244 and/or to a possible displacement of the water molecule involved in the inactivation. From an evolutionary point of view, it is interesting to note that the Staphylococcus aureus enzyme PC1 is highly sensitive to clavulanic acid, although it has an aspartic acid at position 276 as in Streptomyces albus G and other Gram-positive enzymes.^38,49,50 Nevertheless, a full clavulanic acid molecule is bound to the ß-lactamase PC1 active site,⁶² whereas only a part of the inhibitor molecule is bound to the ß-lactamase TEM-1 active site.⁶³

	Conclusions

Top Abstract Introduction Phenotypic characteristics Genetic characteristics Biochemical data Relationship between structure... Conclusions References

 
The emergence of IRT-producing strains might be related to the frequent use of clavulanate-containing formulations in hospitals and in general practice. The IRT-producing strains cannot, however, be detected reliably by routine susceptibility tests. Thus, this characterization must be completed by iso-electric points of ß-lactamases, determination of kinetic parameters,^64,65 and the use of molecular biology techniques.

Genetic studies argue in favour of the convergent evolution of the bla_IRT genes. It seems that such evolution of the parent TEM ß-lactamase to resistance to ß-lactamase inhibitors involves both forward and backward mutations,⁶⁶ as previously suggested for TEM- and SHV-derived extended-spectrum ß-lactamases.⁶⁷ Recently the extended-spectrum ß-lactamases TEM-AQ and TEM-50 (CMT-1) derived from TEM-1, which also have reduced susceptibility to clavulanic acid, provided a new example of convergence in this evolution process.⁶⁸,⁶⁹ On the other hand, inhibitor-resistant ß-lactamases have also been reported in the SHV family.⁷⁰,71

	Notes

 
^* Corresponding author. Tel: +33-2-98908035; Fax: +33-2-98908048; E-mail: roger.labia{at}univ-brest.fr

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Top Abstract Introduction Phenotypic characteristics Genetic characteristics Biochemical data Relationship between structure... Conclusions References

 
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Received 30 June 1998; returned 17 September 1998; revised 26 October 1998; accepted 30 November 1998

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