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Antimicrobial Agents and Chemotherapy, May 2005, p. 1708-1713, Vol. 49, No. 5
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.5.1708-1713.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Genetic Environment and Expression of the Extended-Spectrum ß-Lactamase blaPER-1 Gene in Gram-Negative Bacteria

Laurent Poirel,1 Ludovic Cabanne,1 Haluk Vahaboglu,2 and Patrice Nordmann1*

Service de Bactériologie-Virologie, Hôpital de Bicêtre, Assistance Publique/Hôpitaux de Paris, Faculté de Médecine Paris-Sud, Université Paris XI, 94275 K. Bicêtre, France,1 Infectious Diseases & Clinical Microbiology Department, Kocaeli University Medical School, Kocaeli, Turkey2

Received 22 October 2004/ Returned for modification 6 January 2005/ Accepted 3 February 2005


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ABSTRACT
 
The genetic location of the gene coding for the expanded-spectrum ß-lactamase PER-1 was analyzed in a series of gram-negative isolates. It was identified as part of a composite transposon bracketed by two novel insertion elements, ISPa12 and ISPa13, belonging to the IS4 family that possess transposases that share 63% amino acid identity and that are chromosomally located in Pseudomonas aeruginosa, Providencia stuartii, and Acinetobacter baumannii. On the contrary, the blaPER-1 gene was identified just downstream of an ISPa12 element but not within a composite transposon when it was located on a plasmid in Salmonella enterica serovar Typhimurium and A. baumannii isolates. In both cases, expression of the blaPER-1 gene was driven by promoter sequences located in ISPa12.


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INTRODUCTION
 
The extended-spectrum ß-lactamase (ESBL) PER-1 was first detected in 1993 in a Pseudomonas aeruginosa isolate from a Turkish patient in France (18). This enzyme is weakly related to the other ESBLs and confers resistance to penicillins, cefotaxime, ceftibuten, ceftazidime, and the monobactam aztreonam but spares resistance to carbapenems and cephamycins. Its activity is inhibited by clavulanic acid (17, 18). The blaPER-1 gene is widespread in Acinetobacter spp., P. aeruginosa, and Salmonella enterica serovar Typhimurium in Turkey (29, 30) and has also been detected in Providencia rettgeri in that country (1). In addition, PER-1 has been identified in Acinetobacter sp. isolates in Korea (31) but has rarely been identified in France (24). In Italy, PER-1 was detected in P. aeruginosa, Alcaligenes faecalis, and Proteus mirabilis isolates (19-21).

The ß-lactamase PER-2, which shares 86% amino acid identity with PER-1, was first identified from an S. enterica serovar Typhimurium isolate from Argentina in 1996 (2) and then in other gram-negative bacteria, including S. enterica serovar Senftenberg (27), Klebsiella pneumoniae (15, 26), Enterobacter aerogenes (26), Enterobacter cloacae (26), and Vibrio cholerae (22), in that country.

Whereas the biochemical properties and clinical implications of PER-1-expressing strains have been detailed, the genetic background of the blaPER-1 gene remains unknown. Its location either on the chromosome or on the plasmid has been reported (7, 18). The aim of the present study was to characterize the genetic structures that may explain blaPER-1 gene acquisition in distantly related gram-negative species.


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MATERIALS AND METHODS
 
Bacterial isolates. Five P. aeruginosa, two Acinetobacter baumannii, two S. enterica serovar Typhimurium, and one P. stuartii isolates were included in this study; all of them produced PER-1 (Table 1). They had been identified by using the API 20E and API 32GN systems (bioMérieux, Marcy-l'Etoile, France). Electrocompetent Escherichia coli DH10B (GIBCO BRL, Life Technologies, Cergy Pontoise, France) was used as the recipient strain in transformation experiments.


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  		TABLE 1. PER-1-positive bacterial strains used in this study

PCR amplification for detection of PER-1-encoding gene, class 1 integrons, and sequencing. Under standard PCR conditions (28), primers PER-A and PER-D (Table 2) were used for detection of the blaPER-1 gene. For each reaction, 0.5 µg of whole-cell DNA of the clinical isolates was used. The primers used to detect class 1 integrons were located in the 5' conserved sequence (5'-CS) and in the 3'-CS regions (primers 5'-CS and 3'-CS [Table 2] [12]). A combination of primer 5'-CS or 3'-CS and a primer specific for the blaPER-1 gene was also used to identify the location of blaPER-1 in the integron. The extension step was increased to 6 min, and the amount of Taq polymerase was increased to 6 units per reaction mixture to amplify large DNA fragments. Sequencing of both strands was performed with an automated sequencer (ABI 3100; Applied Biosystems, Foster City, Calif.). The nucleotide and deduced protein sequences were analyzed with software available over the Internet at the National Center for Biotechnology Information website (http://www.ncbi.nlm.nih.gov).


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  		TABLE 2. Primers used in this study

PFGE. Pulsed-field gel electrophoresis (PFGE) analysis was done according to the instructions of the manufacturer (Bio-Rad, Ivry-sur-Seine, France). The XbaI, ApaI, and SpeI restriction enzymes (Amersham Pharmacia Biotech, Orsay, France) were used to genotype the S. enterica serovar Typhimurium, A. baumannii, and P. aeruginosa isolates, respectively, as described previously (19, 24).

Hybridizations. DNA-DNA hybridizations of the PFGE gels were performed by the Southern technique, as described previously (28). The probe consisted of a 927-bp PCR fragment internal to blaPER-1 generated from P. aeruginosa RNL-1 DNA (17). Labeling of the probe and signal detection were carried out with a nonradioactive labeling and detection kit, according to the instructions of the manufacturer (Amersham Pharmacia Biotech).

Electroporation and plasmid DNA content analysis. Plasmid DNA of the bacterial isolates was extracted by the method of Kieser (11). They were electroporated into E. coli DH10B, and recombinant strains were selected on ceftazidime-containing (2 µg/ml) Trypticase soy agar plates.

To search for a chromosomal location of the ß-lactamase gene, we used the endonuclease I-CeuI (New England Biolabs, Ozyme), which digests a 26-bp sequence in the rrn genes for the 23S large-subunit rRNA (13), and separated the fragments by PFGE. Hybridization was performed with two different probes: a 1,504-bp PCR-generated probe specific for the 16S and 23S rRNA genes (9) and a 927-bp probe specific for the blaPER-1 gene, as indicated above.

TAIL-PCR. Three successive amplification reactions were performed with nested primers complementary to known sequences and arbitrary degenerated primers that hybridize to adjacent sequences, as described previously (14). The primers used to obtain the sequences upstream of the blaPER-1 gene were TP.5'ext.1, TP.5'ext.2, and TP.5'ext.3 (Table 2). The products obtained by thermal asymmetric interlaced PCR (TAIL-PCR) were sequenced and analyzed as described above.

Determination of the transcription initiation sites by 5'-RACE. Total RNA was isolated from P. aeruginosa RNL-1 and S. enterica serovar Typhimurium 147 isolates with an Rneasy Midi kit (QIAGEN, Courtaboeuf, France), using the recommendations of the manufacturer. The 5' rapid amplification of cDNA ends (5'-RACE) reactions were performed with 5 µg of total RNA of P. aeruginosa RNL-1 and S. enterica serovar Typhimurium TUR and a 5'-RACE system kit (Version 2.0; Invitrogen), following the recommendations of the manufacturer. The first-strand synthesis was primed with the specific primer TP.5'ext.1, and amplification of the target cDNA was performed with the dC-tailed cDNAs as templates by using the newly described primers TP.5'ext.2 and TP.5'ext.3 (Table 2).

Nucleotide sequence accession number. The nucleotide sequences of the insertion sequences (ISs) reported in this paper have been submitted to the IS Finder Website (http://www-is.biotoul.fr). They have been also deposited in the EMBL/GenBank nucleotide sequence database and have been assigned accession no. AY779042.


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RESULTS
 
Preliminary PCR detection of the blaPER-1 ß-lactamase gene, MICs, and genotyping. The 10 blaPER-1-positive isolates screened by PCR and included in this study were of different geographical origins (Table 1). They belonged to four different gram-negative species (Table 1). The MICs of ß-lactams for the isolates are indicated in Table 3. PFGE analysis with whole-cell DNA of S. enterica serovar Typhimurium, P. aeruginosa, and A. baumannii isolates showed that isolates of a given species were not clonally related (data not shown).


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  		TABLE 3. MICs of ß-lactams for the PER-1-producing P. aeruginosa RNL-1, MUL-2, 1, PER12, and 2622 clinical isolates; the PER-1-producing A. baumannii AMA-1 and C.A. clinical isolates; the S. enterica serovar Typhimurium TUR and 147 clinical isolates; the E. coli DH10B strain harboring natural plasmid pSTI1 from S. enterica serovar Typhimurium 147 expressing PER-1; and the E. coli DH10B reference strain

Chromosomal or plasmid location of the blaPER-1 gene. Transfer of the ceftazidime resistance marker by transformation and extraction of plasmid DNAs suggested that the blaPER-1 gene was chromosomally located in P. aeruginosa and P. stuartii. On the other hand, isolates S. enterica serovar Typhimurium 147 and TUR harbored blaPER-1 on different plasmids (100 and 120 kb, respectively). The chromosomal location of blaPER-1 in isolate P. aeruginosa RNL-1 was confirmed by using the endonuclease I-CeuI technique, which gave a hybridization signal corresponding to a fragment of 900 kb (data not shown). Transformation and plasmid extraction failed to provide evidence of any plasmid in isolate A. baumannii AMA-1, whereas a slight plasmid band (>250 kb) was detected in A. baumannii C.A. Further analysis by the I-CeuI technique revealed that blaPER-1 was chromosomally encoded in isolate A. baumannii AMA-1 (size of the hybridized band, 500 kb) and was plasmid borne in isolate A. baumannii C.A. (data not shown). PCR experiments failed to identify a class 1 integron location of the blaPER-1 gene in these isolates.

Identification of sequences surrounding blaPER-1. By using whole-cell DNAs of P. aeruginosa RNL-1 and S. enterica serovar Typhimurium TUR as templates, TAIL-PCR experiments allowed the identification of the upstream and the downstream regions flanking the blaPER-1 gene. Sequence analysis of the regions flanking the 5' end of the blaPER-1 gene revealed that a novel IS element, ISPa12, was present upstream of blaPER-1 in all the strains studied. Thirteen base pairs separated the left inverted repeat (IRL) of ISPa12 from the blaPER-1 start codon in the five P. aeruginosa isolates, A. baumannii AMA-1, and P. stuartii BEN. This distance was longer in A. baumannii C.A. and in the two S. enterica serovar Typhimurium isolates, since an additional 44-bp fragment was present, indicating that the ISPa12 insertion occurred at different sites upstream of blaPER-1. The latter insertion site was, in fact, detected only in isolates in which blaPER-1 was plasmid borne. The nucleotide sequence identified upstream of the blaPER-1 gene in the P. aeruginosa isolates was identical to that found in a fragment recently characterized in blaPER-1-positive isolate P. aeruginosa Ps101PAT from Italy (19), which also contained at least part of an identical ISPa12 element. It was also similar to the sequence located upstream of the blaPER-2 gene available in the GenBank database, likely indicating that ISPa12 is associated with this blaPER-like gene. In that case, the ISPa12-like element was located 128 bp upstream of the blaPER-2 gene.

The chromosomally encoded blaPER-1 gene is part of composite transposon Tn1213. Analysis of the regions located downstream revealed that blaPER-1 is bracketed by another IS element in the P. aeruginosa isolates and in A. baumannii AMA-1 (Fig. 1). ISPa13 was structurally related to ISPa12 (see below). The ISPa13 element was located 462 bp downstream of the blaPER-1 stop codon. Together with ISPa12, ISPa13 might form a composite transposon, since a duplication of the insertion site was noticed at the left-hand extremity of ISPa12 and at the right-hand extremity of ISPa13 (Fig. 1A). This transposon was named Tn1213, and the direct repeat (DR) sequence generated by its insertion was 8 bp (Fig. 1A). The ISPa12 and ISPa13 elements were inserted in direct orientations like transposase genes and were transcribed in the same orientation. Thus, the IRL of Tn1213 corresponded to the right inverted repeat (IRR) of ISPa12, whereas the IRR of Tn1213 corresponded to the IRL of ISPa13 (Fig. 1A). Since the sequences of the inverted repeats (IRs) or ISPa12 and ISPa13 (see below) were almost identical, Tn1213 possessed almost perfectly complementary IRs. The 462-bp sequence separating the blaPER-1 gene from the ISPa13 element contained a gene (gst) that had been truncated by the ISPa13 insertion, and the corresponding protein shared 31 and 30% amino acid identities with the glutathione-S-transferases of E. coli and Ralstonia solanacearum, respectively.



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  		FIG. 1. Schematic map of the blaPER-1-containing structures identified in P. aeruginosa and A. baumannii AMA-1 isolates (A), P. stuartii BEN (B), and two S. enterica serovar Typhimurium isolates and A. baumannii C.A. (C). The in silico-identified structure in a PER-2-producing S. enterica serovar Typhimurium isolate (GenBank accession no. X93314) is indicated for comparison (D). The genes and their corresponding transcriptional orientations are indicated by horizontal arrows. The DR sequences generated by transposition events are indicated by white triangles for ISPa12, grey triangles for ISPrst1, and black triangles for composite transposon Tn1213. The glutathione-S-transferase gene (gst) and the ABC-type multidrug transporter gene (abct) are also indicated. Arrows indicate the primers used in this study, as indicated in Table 2.

The Tn1213 sequence in P. stuartii BEN was also identified; but it contained an additional element, ISPrst1, a novel IS that had been inserted just downstream of the blaPER-1 gene, which truncated the glutathione-S-transferase gene (Fig. 1B). Since a target site sequence duplication was evidenced in both extremities of ISPrst1 (see above), it is likely that transposition of this element has occurred in the Tn1213 transposon backbone.

Analysis of Tn1213-surrounding sequences in P. aeruginosa isolates, A. baumannii AMA-1, and P. stuartii BEN revealed that the transposition of Tn1213 had occurred inside an IS element named ISPa14 by interrupting its transposase gene (Fig. 1B). This IS element was very similar to ISAba3, which belongs to the IS1 family and which was recently identified in an A. baumannii clinical isolate (25). Their transposases shared 95% amino acid identity over 145 amino acids, but the transposase of ISPa14 was much longer (233 amino acids).

The blaPER-1 gene is not always part of Tn1213. Analysis of the ISPa12 insertion sites revealed a target site duplication (see above) in the two S. enterica serovar Typhimurium isolates and in isolate A. baumannii C.A., in which the blaPER-1 gene was plasmid located (Fig. 1C). This suggests that transposition of ISPa12 occurs independently of blaPER-1 gene acquisition. Analysis of the 600-bp ISPa12 sequence located upstream revealed an open reading frame encoding a putative RNase E that shared 30% identity with that of P. aeruginosa PAO1. PCRs failed to identify ISPa13 in these isolates, confirming the absence of a Tn1213 structure. The glutathione-S-transferase-encoding gene identified in part in Tn1213 was also present and was not truncated; it encoded a putative protein 191 amino acids long. Another gene (abct) encoding a 105-amino-acid protein was identified downstream of this gene. It shared 90 and 87% identities with the ABC-type proteins for multidrug transporters of Shewanella oneidensis and Vibrio cholerae, respectively (Fig. 1).

ISPa12, ISPa13, and ISPrst1 belong to the IS4 family. ISPa12 is 1,387 bp long, and its transposase shares 43% identity with that of ISH8E from a Halobacterium sp. (16). The IRs of ISPa12 are likely 11 bp, and it is noteworthy that they are able to form a hairpin structure (Fig. 2). Transposition of ISPa12 generated an 8-bp duplication at its insertion site in S. enterica serovar Typhimurium isolates, whereas no DR sequence bracketing this element was evidenced in P. aeruginosa. These structural features defined ISPa12 as a member of the IS4 family, which is considered a heterogeneous family, since it gathers distantly related IS elements (5).



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  		FIG. 2. Nucleotide sequences of the regions identified upstream of the blaPER-1 gene in P. aeruginosa RNL-1 (A) and S. enterica serovar Typhimurium 147 (B), with the latter sequence possessing an additional 44-bp fragment. The +1 transcription start site and the –35 and –10 sequences of the PPa and PSt promoters are indicated in boldface and are double underlined. The N-terminal amino acid sequences of the PER-1 ß-lactamase and the transposase of ISPa12 are designated in single-letter code below the nucleotide sequence. The IRL of ISPa12 is shaded in grey, and the 8-bp DR sequence observed in the S. enterica serovar Typhimurium isolate is boxed.

Similarly, ISPa13 is also 1,387 bp and is a member of the IS4 family. Its transposase shares 63% amino acid identity with that of ISPa12. The IRs of ISPa13 are 12 bp and have a single mismatch. The IRR sequence of ISPa13 was identical to that of ISPa12 when 11 of the 12 bp of their extremities was taken in account. Thus, ISPa12 and ISPa13 are structurally related and are able to form a composite transposon.

ISPrst1 is 1,512 bp, and its transposase shares 54% amino acid identity with that of IS50R, which is also a member of the IS4 family (10). Its IRs are likely 21 bp (with three mismatches in the middle of the sequence). The ISPrst1 insertion generated a 9-bp duplication inside the glutathione-S-transferase-like enzyme-encoding gene located just downstream of blaPER-1 in the P. stuartii isolate.

ISPa12 enhances blaPER-1 expression. By using the 5'-RACE PCR technique, the sites of the initiation of transcription of the blaPER-1 gene were mapped in isolates P. aeruginosa RNL-1 and S. enterica serovar Typhimurium 147. The +1 transcription start was located 112 bp upstream of the start codon of the blaPER-1 gene in P. aeruginosa (Fig. 2). Upstream of this transcriptional start site, a –35 sequence (TTCAAA) separated by 17 bp from a –10 sequence (TAATCT) constituted a PPa promoter (Fig. 2). These promoter sequences as well as the +1 signal were part of the ISPa12 element. In S. enterica serovar Typhimurium, the nucleotide sequence of the 5' RACE PCR product showed that the +1 transcription start site was different, since it was located 45 bp upstream of the start codon of blaPER-1 (Fig. 2). Upstream of this transcriptional start site, a –35 sequence (TTCAAA) separated by 16 bp from a –10 sequence (TAAGAA) formed another PSt promoter (Fig. 2). In that case, the –35 promoter sequence belonged to ISPa12, the –10 motif overlapped the IRL of ISPa12, and the +1 signal was part of the sequence flanking the 5' end of the blaPER-1 gene, which was absent in P. aeruginosa.


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DISCUSSION
 
This work characterized the genetic bases of the acquisition of the ß-lactamase PER-1-encoding gene and its expression. Unlike other non-TEM, non-SHV ESBL genes, such as those that code for VEB- or GES-type ß-lactamases, the blaPER-1 gene was not identified as a gene cassette and was not located inside a class 1 integron. However, it was part of a transposon-related structure. blaPER-1-containing transposon Tn1213 was detected in several species from distinct geographical origins.

This report is the first description of a ß-lactamase-mediated composite transposon composed of two different IS elements, both of which belong to the IS4 family. As is known to be the case for composite transposons, it is possible that only a single transposase (likely that of ISPa12) might be functional in the ISPa12/ISPa13 transposon, thus preventing overproduction of the transposase. Further in vitro mobilization experiments will be necessary to assess this hypothesis.

Interestingly, the sequences surrounding the blaPER-1 gene may be different from one species to another in a given country. In addition, comparison of the structures of the sequences surrounding blaPER-1 in the variety of these isolates may indicate the subsequent events: (i) insertion of ISPa12 upstream of blaPER-1 (Fig. 1C); (ii) followed by insertion of ISPa13 downstream of blaPER-1, which forms transposon Tn1213 (Fig. 1A); and finally, (iii) insertion of ISPrst1 inside Tn1213 (Fig. 1B).

Since the location of composite transposon Tn1213 was always inside the ISPa14 element, these results suggest that Tn1213 was not acquired separately in the strains studied but was likely associated with a larger structure, such as a transposon. This association with ISPa14, which is very similar to ISAba3 identified in A. baumannii isolates recovered from several countries (personal data), might suggest that the entire structure may have been acquired first in A. baumannii and then in P. aeruginosa.

ISPa12 drove the expression of the blaPER-1 gene in S. enterica serovar Typhimurium and P. aeruginosa by bringing promoter sequences. Interestingly, these promoter sequences are different in these two species; and the +1 transcription initiation start site was located 45 bp upstream of the start codon of blaPER-1 in S. enterica serovar Typhimurium, whereas it was located 112 bp upstream of the start codon of blaPER-1 in P. aeruginosa. Although the –35 promoter sequences were identical in both isolates, the sequences of their –10 regions differed.

Since recombinant plasmids expressing the blaPER-1 gene in E. coli were difficult to obtain, it is likely that the hairpin structure provided by the IRL of ISPa12 upstream of blaPER-1 may limit the cloning efficiency. However, it is likely that high-level expression of the blaPER-1 gene in vivo may necessitate the presence of ISPa12. Identification of a progenitor that weakly expresses blaPER-1 may be difficult, as has been observed for blaCTX-M genes originating from ß-lactam-susceptible Kluyvera species (8, 23). Identification of similar mobile structures upstream of the blaPER-1 and the blaPER-2 genes would indicate their common origin. This result was observed with CTX-M-type ß-lactamase genes, in which an identical ISEcp1 element was identified upstream of different blaCTX-M genes originating from distinct Kluyvera species (3). Finally, the association between ISPa12 and blaPER-1 adds to the diversity of IS elements that are sources of ß-lactamase expression.


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ACKNOWLEDGMENTS
 
This work was funded by a grant from the Ministère de l'Education Nationale et de la Recherche (grant UPRES-EA3539), Université Paris XI, France, and by the European Community (6th PCRD, grant LSHM-CT-2003-503-335). L.P. is a researcher from INSERM, France.

We thank C. Bal and Z. Aktas for the gift of P. aeruginosa 1, G. Claeys for the gift of P. aeruginosa PER12, and M. Gniadkowski for the gift of P. aeruginosa 2622. We are indebted to M. F. Lartigue, who isolated the P. stuartii BEN strain. We also thank P. Séguier and M. Chandler for helpful discussions.


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FOOTNOTES
 
* Corresponding author. Mailing address: Service de Bactériologie-Virologie, Hôpital de Bicêtre, 78 rue du Général Leclerc, 94275 Le Kremlin-Bicêtre Cedex, 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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Antimicrobial Agents and Chemotherapy, May 2005, p. 1708-1713, Vol. 49, No. 5
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.5.1708-1713.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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