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Antimicrobial Agents and Chemotherapy, February 2003, p. 755-758, Vol. 47, No. 2
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.2.755-758.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Emergence in Klebsiella pneumoniae of a Chromosome-Encoded SHV ß-Lactamase That Compromises the Efficacy of Imipenem

Laurent Poirel,1 Claire Héritier,1 Isabelle Podglajen,2 Wladimir Sougakoff,2 Laurent Gutmann,2 and Patrice Nordmann1*

Service de Bactériologie-Virologie, Hôpital de Bicêtre, Assistance Publique/Hôpitaux de Paris, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre,1 Laboratoire de Recherche Moléculaire sur les Antibiotiques, INSERM, Université Paris VI, Paris, France2

Received 19 June 2002/ Returned for modification 8 September 2002/ Accepted 10 November 2002


   ABSTRACT
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
A Klebsiella pneumoniae isolate was identified that had reduced susceptibility to several expanded-spectrum cephalosporins and imipenem. That isolate produced a chromosome-encoded SHV-type ß-lactamase, SHV-38, that had an alanine to valine substitution in position Ambler 146 compared to ß-lactamase SHV-1. The kinetic parameters for purified ß-lactamases SHV-38 and SHV-1 showed that the hydrolytic spectrum of SHV-38 included only ceftazidime and imipenem. This report is the first example of an SHV-type ß-lactamase capable of hydrolyzing imipenem.


   INTRODUCTION
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Extended-spectrum ß-lactamase (ESBL) production is one of the main mechanisms of resistance to broad-spectrum ß-lactam antibiotics among the Enterobacteriaceae (16). These enzymes are frequently encoded by conjugative plasmids and have evolved from the narrow-spectrum TEM-1 or TEM-2 and SHV-1 penicillinases through point mutations in regions critical for ß-lactam binding and/or hydrolysis (16). They were reported recently as a plague of plasmids (7). ESBLs have spread worldwide, with prevalence and enterobacterial species distribution depending on the geographical situation (4, 16, 17). A surveillance study conducted across the United States indicated increased MICs (2 µg/ml or more) of ceftazidime for 15% of Escherichia coli and 24% of Klebsiella pneumoniae isolates, consistent with an ESBL phenotype (10).

Since the hydrolytic profile of ESBLs includes expanded-spectrum cephalosporins (cefotaxime, ceftazidime, cefepime, and cefpirome), the use of these cephalosporins for treating serious infections caused by an isolate with a confirmed ESBL phenotype should be avoided (12, 18). The mortality rate in patients who have such infections and who are treated with expanded-spectrum cephalosporins is high, and imipenem remains one of the very few ß-lactams left for treating such infections (12, 18).

We report a novel point mutant derivative of the chromosome-encoded SHV-1 of K. pneumoniae that had a substrate profile extending not only to expanded-spectrum cephalosporins but also to imipenem.


   MATERIALS AND METHODS
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Bacterial strains. K. pneumoniae strain Lor-1 was a clinical isolate. E. coli DH10B (Life Technologies, Eragny, France) was used as a recipient strain in electroporation and for protein expression experiments. E. coli K-12 (a gift from P. Plésiat) and K. pneumoniae CIP53513 (Institut Pasteur Paris strain collection) were used as reference strains for endonuclease I-CeuI digestion and susceptibility testing, respectively.

Antimicrobial agents and resistance studies. The antimicrobial agents used and their sources were described previously (20). Antibiotic disks (Sanofi Diagnostics Pasteur, Marnes-la-Coquette, France) were used for routine antibiograms (http://www.sfm.asso.fr). MICs were determined by an agar dilution technique on Mueller-Hinton agar (Sanofi) with an inoculum of 104 CFU per spot (20).

Nucleic acid techniques. Whole-cell DNAs of K. pneumoniae Lor-1 and E. coli K-12 were extracted as described previously (20). Then, Sau3AI-digested DNA fragments of K. pneumoniae Lor-1 were ligated into the BamHI site of phagemid pBK-CMV (20, 21). Recombinant plasmids were transformed by electroporation into E. coli DH10B (19). Antibiotic-resistant colonies were selected on Trypticase soy (TS) agar plates containing amoxicillin (100 µg/ml) and kanamycin (30 µg/ml). Recombinant plasmid DNAs were obtained from cultures of 100 ml of TS broth grown overnight in the presence of amoxicillin (100 µg/ml) at 37°C. Plasmid DNA was extracted and purified with a Qiagen (Courtaboeuf, France) plasmid DNA maxikit. Sequencing of the insert of one of the recombinant plasmids, pLP-1, which carried the novel ß-lactamase gene blaSHV-38, was performed and the results were analyzed as described previously (20). E xtraction of plasmid DNA from K. pneumoniae Lor-1 was attempted as previously reported (20).

A site-directed mutagenesis protocol was used as described by the manufacturer (Quick Change site-directed mutagenesis protocol; Stratagene, La Jolla, Calif.) for changing a T nucleotide to a C at position 425 of the gene to substitute a valine for an alanine residue at position Ambler 146 of the sequenced ß-lactamase. Recombinant plasmid pLP-1 was used as a template with primer SHV-V146A1 (5'-CCACCGTCGGCGGCCCCGCAGGATTGACTGCC-3') andprimer SHV-V146A2 (5'-GGCAGTCAATCCTGCGGGGCCGACGGTGG-3') to generate recombinant plasmid pLP-2. The insert of recombinant plasmid pLP-2 was also checked by sequencing.

To identify the chromosomal location of blaSHV-38 in K. pneumoniae Lor-1, endonuclease I-CeuI (Ozyme; New England Biolabs, Saint-Quentin-en-Yvelines, France) was used to digest 26 bp of the rrn genes, coding for the 23S large-subunit rRNA (13). After digestion, separation of the resulting fragments by pulsed-field gel electrophoresis was performed with a CHEF-DRII apparatus (Bio-Rad) (24). The sizes of the endonuclease I-CeuI-generated fragments were determined by comparison with those of E. coli K-12 (13). After transfer to a nylon membrane (Hybond N+; Amersham Pharmacia Biotech, Orsay, France) according to the Southern technique (24), these fragments were UV cross-linked (Stratalinker; Stratagene Inc.) for 2 min. Then, they were hybridized with two different probes: a PCR-generated 1,502-bp probe for 16S rRNA genes of enterobacterial species (primers A and B) (2) and a PCR-generated 300-bp internal fragment of blaSHV-1 (20). Additionally, NotI- and HindIII-digested DNA of K. pneumoniae Lor-1 was subjected to gel electrophoresis as described previously (20), transferred by the Southern technique, and hybridized with the blaSHV-1 probe. A nonradioactive labeling and detection kit (enhanced chemiluminescence kit) was used (20).

The potential effect of the amino acid substitution found in SHV-38 on the protein structure was explored by using the Swiss PDB Viewer (8).

Biochemical analysis. Cultures of E. coli DH10B harboring recombinant plasmids pLP-1 (SHV-38) and pLP-2 (SHV-1) were grown overnight at 37°C in 4 liters of TS broth containing amoxicillin (100 µg/ml) and kanamycin (30 µg/ml). ß-Lactamase extracts were obtained after sonication as described previously (20). They were dialyzed overnight against 20 mM Tris-HCl buffer (pH 7.9), loaded onto a Sepharose column preequilibrated with the same buffer, and eluted with a linear NaCl gradient (0 to 1 M). The fractions containing the highest ß-lactamase activity were pooled and dialyzed overnight against 20 mM diethanolamine (pH 9.3) prior to a further purification step with a Q-Sepharose column. Final purification was obtained in two successive steps by using Centrisart (10 and 100 kDa; Sartorius, Göttingen, Germany). The protein contents and specific ß-lactamase activities of the enzymes were determined as described previously (20). The purity of the enzymes was estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis as described previously (24). Purified enzymes and ß-lactamase extracts from cultures of K. pneumoniae Lor-1 were subjected to analytical isoelectric focusing (IEF) as previously described (20).

The kinetic parameters for purified ß-lactamases SHV-38 and SHV-1 were determined by UV spectrophotometry as described previously (21). Briefly, kcat and Km values were determined by analyzing ß-lactam hydrolysis under initial rate conditions by using the Eadie-Hofstee linearization of the Michaelis-Menten equation. In the presence of low Km values, Ki values were determined by using amoxicillin as a ß-lactam competitor. Various concentration of ß-lactamase inhibitors were preincubated with the enzymes for 3 min at 30°C before the rate of benzylpenicillin (100 µmol) hydrolysis was tested. The 50% inhibitory concentrations of these inhibitors were determined as the concentrations of these inhibitors that inhibited hydrolytic activity by 50%. Results were expressed in micromolar units.

Nucleotide sequence accession number. The nucleotide sequence of blaSHV-38 has been assigned GenBank accession number AY079099.


   RESULTS
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Clinical case. K. pneumoniae Lor-1 was isolated from a 61-year-old man hospitalized for pancreatitis in the surgical intensive care unit at the hospital Europeen Georges Pompidou (Paris, France) in February 2001. This isolate was from a blood culture and a digestive drain sample. The case history revealed previous treatment with amoxicillin-clavulanic acid, piperacillin-tazobactam, and gentamicin. Following the isolation of K. pneumoniae Lor-1, the patient was treated with cefotaxime and ciprofloxacin, to which the strain appeared susceptible in vitro, according to the results of disk diffusion testing. He has continued to do well after a 10-day antibiotic course.

Genetics. Recombinant plasmid pLP-1 was obtained by cloning of Sau3AI-restricted fragments of whole-cell DNA of K. pneumoniae Lor-1 into plasmid pBK-CMV. Sequencing of the 1,711-bp insert of pLP-1 identified an open reading frame that encoded an Ambler class A ß-lactamase (1). The deduced protein, designated SHV-38, had one amino acid substitution (alanine to valine at position 146, according to the Ambler numbering) (1) compared to SHV-1 (3). Plasmid detection in K. pneumoniae Lor-1 failed. Hybridization of single HindIII and single NotI restriction fragments of whole-cell DNA of K. pneumoniae Lor-1 with a blaSHV-1 probe suggested that this isolate had a single copy of the blaSHV-38 gene (data not shown).

The location of blaSHV-38 was assessed by using the endonuclease I-CeuI technique. Five fragments were generated from restricted DNA of K. pneumoniae Lor-1 (2,200, 1,000, 600, 400, and 100 kb). The DNA probe for rRNA genes hybridized with all endonuclease I-CeuI fragments, except the 2,200-kb fragment, whereas the blaSHV probe hybridized only with the 600-kb fragment. A chromosomal location of blaSHV-38 was thus indicated. Additionally, the nucleotide sequence of a ca. 900-bp sequence downstream of blaSHV-38 was identical to that reported for blaSHV-1 in K. pneumoniae (6), further indicating the chromosomal origin of blaSHV-38.

A site-directed mutagenesis experiment with pLP-1 as the template yielded plasmid pLP-2, which contained the same insert as pLP-1, except for a T-to-C change leading to a Val-to-Ala change at Ambler position 146. Plasmid pLP-2 encoded ß-lactamase SHV-1.

IEF analysis and susceptibility testing. IEF analysis revealed for K. pneumoniae Lor-1 and E. coli DH10B harboring pLP-1 (SHV-38) or pLP-2 (SHV-1) a single and identical ß-lactamase with a pI of 7.6 (data not shown).

K. pneumoniae Lor-1 was resistant to amino-, carboxy-, and ureidopenicillins with or without ß-lactamase inhibitors and to cephalothin and showed reduced susceptibility to several expanded-spectrum cephalosporins, moxalactam, the monobactam aztreonam, and imipenem (Table 1). Although low, the MIC of imipenem for this isolate was still higher than that for reference strain K. pneumoniae CIP53513 (0.06 µg/ml). The isolate was fully susceptible to cefotaxime and ceftriaxone and showed intermediate susceptibility to ceftazidime (Table 1).


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  		TABLE 1. MICs of ß-lactams for K. pneumoniae Lor-1, E. coli DH10B(pLP-1), E. coli DH10B(pLP-2), and E. coli DH10B (reference strain)

 
Once cloned into a multicopy plasmid and expressed in E. coli DH10B(pLP-1), blaSHV-38 conferred a ß-lactam resistance pattern similar to that found for K. pneumoniae Lor-1, but at a higher resistance level. The MICs of ß-lactams with or without ß-lactamase inhibitors for E. coli DH10B(pLP-2) encoding SHV-1 mirrored those for E. coli DH10B(pLP-1) encoding SHV-38, but at a lower level (Table 1). No reduced susceptibility to most expanded-spectrum cephalosporins and imipenem was observed when SHV-1 was expressed, except for ceftazidime, as reported previously (18). In vitro resistance to inhibitors was observed with strains expressing SHV-1 and SHV-38, as reported for enterobacterial strains producing high levels of ß-lactamase SHV-1 (18). The total activities of crude extracts of E. coli DH10B harboring plasmids pLP-1 (SHV-38) and pLP-2 (SHV-1) and of K. pneumoniae Lor-1 with 100 µM benzylpenicillin as a substrate were 150, 33, and 11 U per mg of protein, respectively. These results explain in part the differences in the MICs that have been observed.

Biochemical analysis. The specific activities of purified ß-lactamases SHV-38 and SHV-1, measured with 100 µM benzylpenicillin as a substrate, were 20 and 100 U per mg of protein, respectively, with a 40-fold purification factor for each. The purity of both was estimated to be >90%. SHV-38 had strong activity against benzylpenicillin, amoxicillin, piperacillin, cephalothin, and cefuroxime (Table 2). Hydrolytic activity was also observed against expanded-spectrum cephalosporins and imipenem, whereas no activity was detected against cefoxitin, moxalactam, and meropenem. As expected (15, 25), SHV-1 had a narrow-spectrum hydrolytic profile, excluding expanded-spectrum cephalosporins (ceftazidime) and imipenem (Table 2).


View this table:
[in this window]
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  		TABLE 2. Kinetic parameters for purified ß-lactamase SHV-38 and purified SHV-1

 
The concentrations of ß-lactamase inhibitors that reduced ß-lactamase activity by 50% were similar for SHV-38 and SHV-1, i.e., 45 and 63 nM for clavulanic acid, respectively, 170 and 150 nM for tazobactam, respectively, and 5 µM for sulbactam for both. Based on its kinetic parameters, ß-lactamase SHV-38 belongs to ß-lactamase group 2be in the Bush-Jacoby-Medeiros classification (5).


   DISCUSSION
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We report here a novel ß-lactamase that is structurally related to the narrow-spectrum penicillinase SHV-1. The blaSHV-38 gene, like blaSHV-1, which is naturally present on the chromosome of K. pneumoniae (6), is also chromosome encoded.

The ß-lactamase SHV-38 is, to the best of our knowledge, the first example of an SHV-1 derivative that has some carbapenem-hydrolyzing activity, considering that none of the plasmid-mediated extended-spectrum SHV and TEM derivatives that have spread worldwide has yet shown such an activity (4, 9, 16, 25). It is also the first example of a chromosome-encoded SHV-type enzyme with an extended hydrolysis profile that also includes, like the other ESBLs of the SHV type, some expanded-spectrum cephalosporins (9, 25).

Reduced susceptibility to carbapenems has been reported for K. pneumoniae and results from the acquisition of a plasmid-mediated class A carbapenem-hydrolyzing ß-lactamase (KPC-1) (27); from metalloenzymes, which are distantly related to SHV-type ß-lactamases (26); or from mechanisms combining decreased outer membrane permeability and the expression of plasmid-mediated AmpC-type ß-lactamases and ESBLs (14). In none of these examples is the ß-lactamase involved structurally related to the naturally expressed penicillinase of K. pneumoniae. Although quite low, the level of resistance to imipenem of SHV-38-producing K. pneumoniae Lor-1 was similar to that reported for several K. pneumoniae clinical isolates and E. coli reference strains that had metallocarbapenemase genes (22, 26). The penicillinase SHV-38 conferred some degree of resistance to moxalactam without detectable hydrolysis, a peculiar property for an ESBL that is shared by the ESBL TEM-52 (23). The kinetic parameters of SHV-38 and SHV-1 may explain in part the MICs obtained for SHV-38-producing strains. A difference in overall ß-lactamase activity between SHV-38 and SHV-1 producers may explain the observed difference in the MICs of ß-lactams as well as better in vivo stability of SHV-38.

The Ala146Val amino acid substitution has not been reported in any TEM- or SHV-type ß-lactamases (http://www.lahey.org/studies/webt.htm). According to an analysis of the crystal structure of SHV-1 (11), this change does not occur in either the ß-lactam binding site or the catalytic site of this enzyme. It is located at the N terminus of an alpha helix lying parallel to the region from positions 161 to 164 of the omega loop structure known to play a key role in ß-lactam hydrolysis (11, 25). The way in which the Ala146Val substitution alters the behavior of the mutant enzyme remains unclear. Indeed, the side chain of residue 146 is oriented toward the solvent, so that it does not establish direct contacts with other residues in the protein. However, because it occupies a position highly exposed to the solvent, the side chain of Val-146, a hydrophobic residue preferentially found in the inside of proteins, may significantly disturb the conformation of the N-terminal part of the helix, with possible consequences for the neighboring omega loop located only 3.1 Å away.

Since the SHV-type enzymes, apart from being naturally chromosome encoded, may also be plasmid encoded (9, 25) and since K. pneumoniae is known to be an efficient vehicle for transmitting ESBL genes (4, 7, 16), it may also support the dispersion of this novel type of ß-lactamase. Indeed, another patient hospitalized concomitantly in the same intensive care unit was found to be infected by the same SHV-38 producer. Finally, the emergence of SHV-38 may constitute a first step in the selection of higher-level carbapenem-resistant enterobacterial strains. Treatment of infections due to SHV-38-expressing strains with imipenem should probably be done with caution, since high inocula may be present at the infection site and may raise further the MIC of imipenem.


   ACKNOWLEDGMENTS
 
We thank E. Collatz for critical reading of the manuscript.

This work was funded by a grant from the Ministères de l'Education Nationale et de la Recherche (UPRES-EA 3539), Université Paris XI, Paris, France.


   FOOTNOTES
 
* Corresponding author. Mailing address: Service de Bactériologie-Virologie, Hôpital de Bicêtre, 78, Rue du Général Leclerc, 94275 Le Kremlin-Bicêtre, France. Phone: 33 1 45 21 36 32. Fax: 33 1 45 21 63 40. E-mail: nordmann.patrice{at}bct.ap-hop-paris.fr. Back


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 Discussion
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Antimicrobial Agents and Chemotherapy, February 2003, p. 755-758, Vol. 47, No. 2
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.2.755-758.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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