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Antimicrobial Agents and Chemotherapy, May 1998, p. 1110-1114, Vol. 42, No. 5
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Chromosomally Encoded AmpC-Type beta -Lactamase in a Clinical Isolate of Proteus mirabilis

L. Bret,1,* C. Chanal-Claris,1 D. Sirot,1 E. B. Chaibi,2 R. Labia,2 and J. Sirot1

Laboratoire de Bactériologie, Faculté de Médecine, 63001 Clermont-Ferrand Cedex,1 and UMR 175, CNRS-MNHN, 29000 Quimper,2 France

Received 30 July 1997/Returned for modification 30 November 1997/Accepted 8 March 1998

    ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

A clinical strain of Proteus mirabilis (CF09) isolated from urine specimens of a patient displayed resistance to amoxicillin (MIC >4,096 µg/ml), ticarcillin (4,096 µg/ml), cefoxitin (64 µg/ml), cefotaxime (256 µg/ml), and ceftazidime (128 µg/ml) and required an elevated MIC of aztreonam (4 µg/ml). Clavulanic acid did not act synergistically with cephalosporins. Two beta -lactamases with apparent pIs of 5.6 and 9.0 were identified by isoelectric focusing on a gel. Substrate and inhibition profiles were characteristic of an AmpC-type beta -lactamase with a pI of 9.0. Amplification by PCR with primers for ampC genes (Escherichia coli, Enterobacter cloacae, and Citrobacter freundii) of a 756-bp DNA fragment from strain CF09 was obtained only with C. freundii-specific primers. Hybridization results showed that the ampC gene is only chromosomally located while the TEM gene is plasmid located. After cloning of the gene, analysis of the complete nucleotide sequence (1,146 bp) showed that this ampC gene is close to blaCMY-2, from which it differs by three point mutations leading to amino acid substitutions Glu right-arrow Gly at position 22, Trp right-arrow Arg at position 201, and Ser right-arrow Asn at position 343. AmpC beta -lactamases derived from that of C. freundii (LAT-1, LAT-2, BIL-1, and CMY-2) have been found in Klebsiella pneumoniae, E. coli, and Enterobacter aerogenes and have been reported to be plasmid borne. This is the first example of a chromosomally encoded AmpC-type beta -lactamase observed in P. mirabilis. We suggest that it be designated CMY-3.

    INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

Resistance to beta -lactams in Proteus mirabilis strains is principally due to TEM production, with a high prevalence of TEM-2 (26). Extended-spectrum beta -lactamases TEM-3 (10, 24), TEM-10 (27), or PER-2 (4) and, recently, inhibitor-resistant TEM (IRT-13/TEM-44) (8) have also been observed in this species. Chromosomal cephalosporinase has not been reported in P. mirabilis strains. Bush group 1 beta -lactamases (9) are encoded by chromosomally located bla genes in Enterobacteriaceae, principally in Enterobacter, Serratia, Citrobacter, and Providencia species and Escherichia coli. These enzymes, belonging to class C beta -lactamases (1), are cephalosporinases not inhibited by clavulanic acid. Plasmid-mediated class C beta -lactamases have been recently reported in Klebsiella pneumoniae (3, 5, 7, 13-15, 28, 34), E. coli (7, 11) Enterobacter aerogenes (13), and Salmonella species (2, 18). These beta -lactamases show sequence similarities to AmpC beta -lactamases either of Enterobacter cloacae (ACT-1, and MIR-1) (7, 28), of Citrobacter freundii (CMY-2, BIL-1, LAT-2, and LAT-1) (3, 11, 13, 34), or of Pseudomonas aeruginosa (CMY-1, FOX-1, and MOX-1) (5, 14, 15).

We describe here a chromosomally encoded class C beta -lactamase that may be derived from AmpC beta -lactamase of C. freundii, produced by a clinical strain of P. mirabilis resistant to all penicillins and cephalosporins, including cephamycins and aztreonam.

    MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

Bacterial strains. P. mirabilis CF09, producing TEM-2 and the novel beta -lactamase, was isolated from urine specimens of a patient hospitalized in a neurology unit of the teaching hospital of Clermont-Ferrand (France). P. mirabilis ATCC 103181T and E. coli JM109 were used as recipient strains, respectively, for transfer experiments by conjugation and for transformation after cloning experiments. C. freundii OS60, E. cloacae P99, and E. coli K-12 were used as positive controls for DNA amplification by PCR with ampC-specific primers. E. coli RP4 (TEM-2) and C. freundii OS60 were used as positive controls, and P. mirabilis ATCC 103181T was used as a negative control for DNA-DNA hybridizations.

Susceptibility to beta -lactams. MICs of amoxicillin, amoxicillin-clavulanic acid (clavulanic acid at a fixed concentration of 2 µg/ml), ticarcillin, ticarcillin-clavulanic acid (clavulanic acid at a fixed concentration of 2 µg/ml), cephalothin, cefoxitin, cefotaxime, ceftazidime, aztreonam, and imipenem were determined by dilution in Mueller-Hinton agar (Sanofi Diagnostics Pasteur, Marnes-la-Coquette, France) with an inoculum of 104 CFU per spot. Antibiotics were provided as powders by SmithKline Beecham Pharmaceuticals (amoxicillin, ticarcillin, and clavulanic acid), Roussel-Uclaf (cefotaxime), Glaxo Wellcome Research and Development (ceftazidime), Bristol-Myers Squibb (aztreonam), and Merck Sharp and Dohme-Chibret (cefoxitin and imipenem).

Isoelectric focusing. Isoelectric focusing was performed with polyacrylamide gels containing ampholines with a pH range of 3.5 to 10, as previously described (32). beta -Lactamases with known pIs, TEM-1 (5.4), TEM-2 (5.6), SHV-5 (8.2), and MEN-1 (8.6), were used as standards.

Conjugation experiments. Conjugation experiments were performed for 40 min at 37°C for strain CF09 with recipient strain P. mirabilis ATCC 103181T, resistant to rifampin. The transconjugants were selected on agar containing rifampin (300 µg/ml) and ceftazidime (16 µg/ml) and on agar containing rifampin (300 µg/ml) and ticarcillin (128 µg/ml).

Determination of beta -lactamase kinetic constants Km, Ki, and relative Vmax. Affinity Km and relative Vmax values were obtained with highly purified extracts (>= 97% pure) by a computerized microacidimetric method (19). The Km and relative Vmax values of the AmpC-type beta -lactamase produced by P. mirabilis CF09 were determined for penicillins and cephalosporins. The inhibition constants (Ki) with clavulanic acid, sulbactam, and tazobactam were determined by competition procedures with cephaloridine.

DNA amplification. DNA amplification with crude extract of P. mirabilis CF09 as a template was performed by PCR (29) in a Perkin-Elmer GeneAmp PCR System 2004 DNA thermal cycler (Perkin-Elmer Cetus Instruments) with a symmetric ratio of consensus primers CF-A and CF-B, specific for the ampC genes of C. freundii, consensus primers EC-A and EC-B, specific for the ampC genes of E. cloacae, primers COL-A and COL-B, specific for the ampC gene of E. coli K-12 (Table 1), and primers 5'-CS and 3'-CS, specific for the 5' and 3' conserved segments of integrons previously described (20). Annealing temperatures were 54°C for primers CF-A and CF-B, 62°C for primers EC-A and EC-B, 58°C for primers COL-A and COL-B, and 50°C for primers 5'-CS and 3'-CS.

                              
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  		TABLE 1.   Nucleotide sequences of the oligonucleotides used for amplification and/or sequencing reactions

DNA preparation. Plasmid DNA preparation was performed by alkaline lysis, as previously described by Kado and Liu (17). Chromosomal DNA preparation was performed by lysis with lysozyme, proteinase K, and Sarkosyl, as described by Sambrook et al. (30). Chromosomal DNA was obtained by centrifugation in a cesium chloride density gradient with phenylmethylsulfonyl fluoride at a concentration of 50 µg/ml. The viscous fraction containing chromosomal DNA was collected by dripping through a large needle inserted into the side of the tube and dialyzed.

Probe preparation. A blaTEM internal fragment of 328 bp was amplified as previously described (32). An ampC 756-bp DNA fragment was amplified by PCR with C. freundii OS60 as the template and with ampC-specific primers CF-A and CF-B. These two probes were labeled with [alpha -32P]dATP, as previously described (32).

DNA-DNA hybridizations. Total chromosomal and plasmid DNA from P. mirabilis CF09 were hybridized with the blaTEM and ampC probes, as previously described (32), by dot blotting on a nylon membrane (Hybond-N; Amersham International). E. coli RP4 (TEM-2) and C. freundii OS60 were used as positive controls, and P. mirabilis ATCC 103181T was used as a negative control.

Cloning experiments. Cloning experiments were performed as described by Sambrook et al. (30). CF09 chromosomal DNA was digested with HindIII (Boehringer Mannheim, Meylan, France). Ligation to vector pACYC 184 was followed by electrotransformation of E. coli JM109. E. coli transformants were selected on Mueller-Hinton agar containing ceftazidime (16 µg/ml) and chloramphenicol (25 µg/ml).

Sequencing. Sequencing of the internal 756-bp DNA fragment was performed by the dideoxy chain termination procedure of Sanger et al. (31) on an ABI377 automatic sequencer using the ABI PRISM Dye Terminator Cycle Sequencing Ready Reaction kit with AmpliTaq DNA polymerase FS (Perkin-Elmer/Applied Biosystems division, Foster City, Calif.) and primers CF-A and CF-B (Table 1). Complete sequencing of the gene and of the flanking regions was obtained with primers CF-C and CF-D (Table 1), whose sequences were determined from the nucleotide sequence of the internal 756-bp DNA fragment.

    RESULTS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

Cloning experiments. An E. coli JM109 clone harboring a recombinant plasmid with a DNA insert of approximately 5 kb (pPM1) was obtained. This clone, designated E. coli JM109(pPM1), was kept for further analysis. Resistance phenotyping, isoelectric focusing, and amplification by PCR with C. freundii ampC-specific primers (CF-A and CF-B) confirmed the presence of the ampC gene in E. coli JM109(pPM1).

Conjugation experiments. Plasmid DNA from P. mirabilis CF09 was transferred by conjugation into P. mirabilis ATCC 103181T. A transconjugant (TrCF029) was obtained only on agar containing rifampin and ticarcillin. It was resistant to penicillins, and the bla gene, encoding the beta -lactamase produced, was identical to the blaTEM-2 gene, as confirmed by sequencing (data not shown).

beta -Lactamase characterization. Two beta -lactamase bands, of pI 5.6 and 9.0, were observed by isoelectric focusing in P. mirabilis CF09; only one band, of pI 9.0, in E. coli JM109(pPM1) and one band, of pI 5.6, in the transconjugant TrCF029 were observed.

Susceptibility to beta -lactams. P. mirabilis CF09 and E. coli JM109(pPM1) were characterized by high levels of resistance to cephalothin (>1,024 and >1,024 µg/ml, respectively), cefoxitin (64 and 128 µg/ml), and broad-spectrum cephalosporins (cefotaxime, 256 and 16 µg/ml; ceftazidime, 128 and 64 µg/ml) (Table 2). Clavulanic acid did not act synergistically with cephalosporins for either strain. A low synergistic effect was observed only with penicillins for the clinical strain CF09, which produced a TEM-2 enzyme in addition to the AmpC-type beta -lactamase. The cephalosporin resistance phenotype of E. coli JM109(pPM1) was similar to that of E. coli DH5alpha T+(pPMV2), described elsewhere (3), which produces enzyme CMY-2 (Table 2).

                              
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  		TABLE 2.   MICs of beta -lactams for P. mirabilis CF09, clone E. coli JM109(pPM1) harboring recomibinant plasmid pPM1, recipient strain E. coli JM109, and clone E. coli DH5alpha T+ producing CMY-2 (3).

Kinetic constants. The kinetic parameters (Km, Ki, and Vmax) of the AmpC-type beta -lactamase produced by strain CF09 (Table 3) were similar to those reported for cephalosporin-hydrolyzing beta -lactamases poorly inhibited by clavulanic acid (Bush group 1 beta -lactamases) (9).

                              
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  		TABLE 3.   Kinetic parameters of the beta -lactamase CMY-3

DNA amplification. Amplification of CF09 DNA with the ampC-specific primers was successful only with C. freundii-specific primers CF-A and CF-B (Table 1) and, as expected, a 756-bp DNA fragment was obtained. No DNA amplification was obtained with integron-specific primers 5'-CS and 3'-CS.

Sequencing. The complete nucleotide sequence of the gene encoding the AmpC-type beta -lactamase was obtained with the recombinant plasmid pPM1 and primers CF-A, CF-B, CF-C, and CF-D (Table 1). The nucleotide sequence of this bla gene differs from blaCMY-2 by three point mutations, A right-arrow G at position 167, T right-arrow C at position 703, and G right-arrow A at position 1130, leading to amino acid substitutions Glu right-arrow Gly at position 22, Trp right-arrow Arg at position 201, and Ser right-arrow Asn at position 343 (Table 4). Sequencing of about 1,080 bp of each side of the flanking regions was obtained. No inverted repeated sequences suggestive of a transposable element and no sequences evoking a 59-base element specific to a gene cassette were observed.

                              
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  		TABLE 4.   Nucleotide and amino acid substitutions between blaCMY-2 and  blaCMY-3

DNA-DNA hybridizations. Total DNA of P. mirabilis CF09 hybridized with the blaTEM and the ampC probes. The ampC probe hybridized with chromosomal DNA of strain CF09, and the blaTEM probe hybridized with plasmid DNA of strain CF09 (Fig. 1).


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  		FIG. 1.   DNA-DNA hybridizations, by dot blotting on a nylon membrane, of total, chromosomal, and plasmid DNA from P. mirabilis CF09 with the blaTEM probe (A) and the C. freundii ampC probe (B). 1, Total DNA from strain CF09; 2, chromosomal DNA from strain CF09; 3, plasmid DNA from strain CF09; 4, total DNA from C. freundii OS60; 5, total DNA from E. coli RP4(TEM-2); 6, total DNA from P. mirabilis ATCC 103181T.

    DISCUSSION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

Wild-type strains of P. mirabilis are susceptible to all penicillins and cephalosporins. TEM or TEM-derived beta -lactamases in this species have been previously described, and no chromosomally encoded beta -lactamase production has been reported. The beta -lactamase CEP-1 produced by a clinical strain of P. mirabilis was the first plasmid-mediated AmpC beta -lactamase reported (6), but the nucleotide sequence of the gene encoding this enzyme has not been determined. Since 1990, several plasmid-mediated AmpC-type beta -lactamases have been characterized, mainly in K. pneumoniae (3, 5, 7, 13-15, 28, 34) but also in E. coli (7, 11) E. aerogenes (13), and Salmonella species (2, 18). They confer a beta -lactam resistance phenotype resembling that conferred by derepressed cephalosporinase. This resistance to beta -lactams is not reversed by clavulanic acid. These enzymes originate from the chromosomal AmpC beta -lactamases of C. freundii, E. cloacae, or P. aeruginosa. The enzymes that originate from C. freundii (LAT-1, LAT-2, CMY-2, and BIL-1) or from E. cloacae (MIR-1 and ACT-1) have high homologies, about 90%, with their parent AmpC enzyme (5, 7, 13), while MOX-1, FOX-1, and CMY-1 have homologies of only 55% with the AmpC beta -lactamase of P. aeruginosa (5).

We describe a clinical strain of P. mirabilis which expresses an unusual resistance phenotype, with high-level resistance to beta -lactams and other antibiotics including aminoglycosides (except amikacin), fluoroquinolones, trimethoprim, and sulfamethoxazole. This strain produces two beta -lactamases, a TEM-2 enzyme and an AmpC-type beta -lactamase. Production of this AmpC beta -lactamase by E. coli JM109(pPM1), which harbors the recombinant plasmid pPM1, confers high-level resistance to amoxicillin, amoxicillin-clavulanic acid, ticarcillin, ticarcillin-clavulanic acid, all the cephalosporins investigated, and aztreonam (Table 2). The MICs of cephalosporins for E. coli JM109(pPM1) are similar to those reported by Bauernfeind et al. (3) for E. coli DH5alpha T+(pPMV2), which produces only CMY-2.

The amino acid sequence of the AmpC-type beta -lactamase produced by strain CF09 is close to that of CMY-2, from which it differs by three amino acid substitutions: Glu right-arrow Gly-22, Trp right-arrow Arg-201, and Ser right-arrow Asn-243. It is unlikely that the substitutions of Gly for Glu-22 and Arg for Trp-201, which occur far from the active site, affect the catalytic properties of the enzyme. Substitution of Asn for Ser-343 has been previously described for the amino acid sequences of the chromosomal AmpC beta -lactamases of E. coli K-12 (16) and P. aeruginosa (23) and of plasmid-mediated AmpC beta -lactamases FOX-1 (14) and CMY-1 (5). Although Ser-343 is close to Ser-318, which follows box 7 (KTG triad beginning at position 315) (22, 25), this substitution probably has no effect on catalytic properties.

CMY-2 is a plasmid-mediated AmpC beta -lactamase that has been described for K. pneumoniae and which originates from the chromosomal beta -lactamase of C. freundii (3). A plasmid carrying blaCMY-2 was recently observed in C. freundii and was transferable to K. pneumoniae and E. coli (3), which explains why this gene can be observed in Enterobacteriaceae other than C. freundii. Our results show that the gene encoding the AmpC-type beta -lactamase produced by P. mirabilis CF09 is only chromosomally located. We suggest that the ampC gene migrated like blaCMY-2 from the chromosome of C. freundii to a plasmid with a transposon as the vehicle. This plasmid might be transferred in P. mirabilis CF09; hence, we hypothesize that the CF09 ampC gene could be in turn transposed from the plasmid to the chromosome, as previously suggested for ACT-1 (7). We did not observe a P. mirabilis strain harboring a plasmid encoding the CF09 AmpC beta -lactamase, which suggests that the replication of beta -lactamase-encoding plasmids could be as problematic as their transfer in this species (24).

Preliminary results of sequencing of the flanking regions of the gene encoding the AmpC beta -lactamase produced by strain CF09 (about 1,080 bp on each side) did not show inverted repeated sequences suggestive of the presence of a transposable element. This ampC gene was probably not inserted in an integron, since a short imperfect inverted repeat element called 59-base element (specific to gene cassettes inserted in integron structures) was not observed on the flanking regions. Moreover, amplification by PCR with primers specific to the 5' and 3' conserved segments of integrons was unsuccessful. Further studies on these flanking regions are in progress.

Chromosomal AmpC beta -lactamases of C. freundii or E. cloacae are regulated by a trans-acting protein, AmpR, which is encoded by the ampR gene immediately upstream of the ampC beta -lactamase gene. In the absence of an inducer, AmpR represses the synthesis of the beta -lactamase. No plasmid-mediated AmpC beta -lactamase except DHA-1 (2) has an ampR regulatory gene. Sequencing of the flanking regions of the gene encoding the AmpC beta -lactamase produced by strain CF09, as for blaCMY-2, did not show homology with an ampR regulatory gene. The lack of an ampC regulator could explain the beta -lactam resistance phenotype conferred by the production of these plasmid-mediated beta -lactamases, which is close to that conferred by derepressed cephalosporinase production.

Plasmid-mediated AmpC beta -lactamases have been reported increasingly since 1990, principally in species which do not produce an inductible chromosomal AmpC beta -lactamase. Three outbreaks of Enterobacteriaceae producing AmpC plasmid-mediated beta -lactamases have been reported (7, 13, 28). The other plasmid-mediated AmpC beta -lactamases were observed sporadically (3, 5, 14, 15, 34). Production of these plasmid-mediated enzymes was probably underestimated in C. freundii, Enterobacter species, and Serratia species, owing to the presence of a chromosomal cephalosporinase, which can be derepressed. Hence, detection of a plasmid-mediated AmpC beta -lactamase in these species is more difficult.

This is the first report of an AmpC-type beta -lactamase produced by a clinical strain of P. mirabilis from France. This enzyme, which is only chromosomally, encoded, could be designated CMY-3.

    ACKNOWLEDGMENTS

We thank Rolande Perroux, Marlene Jan, and Dominique Rubio for technical assistance.

This work was supported in part by a grant from the Direction de la Recherche et des Etudes Doctorales, Ministère de l'Education Nationale, Paris, France.

    FOOTNOTES

* Corresponding author. Mailing address: Laboratoire de Bactériologie, Faculté de Médecine, 28 Place Henri-Dunant, 63001 Clermont-Ferrand Cedex, France. Phone: 33 4 73 60 80 18. Fax: 33 4 73 27 74 94. E-mail: Danielle.SIROT{at}U-Clermont1.fr.

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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

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Antimicrobial Agents and Chemotherapy, May 1998, p. 1110-1114, Vol. 42, No. 5
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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