JAC Advance Access originally published online on November 1, 2002
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Journal of Antimicrobial Chemotherapy (2002) 50, 1031-1034
© 2002 The British Society for Antimicrobial Chemotherapy
Biochemical analysis of the ceftazidime-hydrolysing extended-spectrum ß-lactamase CTX-M-15 and of its structurally related ß-lactamase CTX-M-3
1 Service de Bactériologie-Virologie, Hôpital de Bicêtre, Assistance Publique/Hôpitaux de Paris, Faculté de Médecine Paris-Sud, 94275 Le Kremlin-Bicêtre, France; 2 Sera & Vaccines Central Research Laboratory, 00725 Warsaw, Poland
Received 17 July 2002; returned 3 September 2002; revised 10 September 2002; accepted 11 September 2002
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Abstract |
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The extended-spectrum ß-lactamase CTX-M-15 confers resistance to ceftazidime, unlike the majority of CTX-M-type enzymes. Kinetic parameters were determined from purified CTX-M-15 and CTX-M-3, which differ by the single amino acid substitution Asp-240 to Gly, according to the Ambler numbering of class A ß-lactamases. Relative molecular masses of CTX-M-15 and CTX-M-3 were
29 kDa and pI values were 8.9 and 8.4, respectively. CTX-M-15 had higher affinities for ß-lactams (lower Km values) than those of CTX-M-3 but catalytic efficiency (kcat/Km values) was variable depending on the ß-lactam substrate. Only CTX-M-15 showed a measurable catalytic efficiency for ceftazidime. Clavulanic acid and tazobactam were good inhibitors of both enzymes. MICs of ß-lactams for Escherichia coli reference strains expressing cloned ß-lactamase genes in the same genetic background were similar except for ceftazidime. This work underlines the fact that some CTX-M enzymes may hydrolyse ceftazidime and thus confer resistance to this expanded-spectrum cephalosporin in Enterobacteriaceae. Keywords: ß-lactamase, CTX-M, expanded-spectrum ß-lactamases
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Introduction |
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TopAbstractIntroductionMaterials and methodsResults and discussionReferences |
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In addition to the classical TEM and SHV enzymes, sev- eral plasmid-mediated Ambler class A extended-spectrum ß-lactamases (ESBLs) have been reported. Among them, the CTX-M-type ß-lactamases are currently spreading worldwide in Enterobacteriaceae.1 The name ‘CTX-M’ refers to their potent hydrolytic activity for cefotaxime.1,2 The CTX-M enzymes confer high-level resistance to cefotaxime, ceftriaxone and aztreonam, but have only marginal effects on MICs of ceftazidime for both wild-type and laboratory-derived strains of enterobacteria.1 According to amino acid sequence data, they may be grouped in four clusters: CTX-M-1 (CTX-M-1, -3, -10, -11, -12, -15), CTX-M-2 (CTX-M-2, -4, -5, -6, -7, -20, Toho-1), CTX-M-8 and CTX-M-9 (CTX-M-9, -13, -14, -16, -18, -19 and Toho-2) (accession nos AJA16344 and 41346).1–6
Two novel point-mutant derivatives of CTX-M-9, CTX-M-16 and CTX-M-19, have been reported to hydrolyse ceftazidime significantly.3,6 Additionally, we have reported recently the DNA sequence of another ß-lactamase, CTX- M-15, from Indian enterobacterial isolates that were resistant to both cefotaxime and ceftazidime.5 CTX-M-15 has a single amino acid change [Asp-240
Gly (Ambler numbering)]7 compared with CTX-M-3.5 It has so far also been found in Japan (ß-lactamase UOE-1; GenBank accession no. AY013478), Bulgaria8 and Poland,9 where CTX-M-3 is widespread.10
Since CTX-M-15-producing isolates had a significant degree of resistance to ceftazidime,5 we have purified CTX-M-15 and CTX-M-3 and compared their kinetic parameters (kinetics of CTX-M-3 has not been studied before). Additionally, this report provides detailed kinetic data that are available only for a very few CTX-M-type enzymes.
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Materials and methods |
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TopAbstractIntroductionMaterials and methodsResults and discussionReferences |
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Bacterial strains, cloning experiments and sequencing
CTX-M-15-producing Escherichia coli 2 was from India.5 Citrobacter freundii isolate 2526/96, which was identified in Poland in 1996, was used as a blaCTX-M-3-containing strain.4 E. coli reference strain DH10B was used for cloning and expression experiments.6 Cloning was carried out with PCR products generated with primers PROM+ (5'-TGCTCTGTGGATAACTTGC-3') and preCTX-M-3B (5'-CCGTTTCCGCTATTACAAAC-3') annealing to the 3'-end of insertion sequence ISEcp1 located upstream of blaCTX-M-15 and downstream of blaCTX-M-15/-3, respectively (accession no. AY044436).3,4 Whole-cell DNA from E. coli 2 and C. freundii 2526/96 was used as template.5 PCR amplimers were cloned into the SrfI site of the pPCRScript-Cam (SK+) plasmid (Stratagene Inc., La Jolla, CA, USA). Recombinant plasmids were transformed into electrocompetent E. coli DH10B cells and selected on Mueller–Hinton (MH) agar plates containing 100 mg/L ampicillin and 30 mg/L chloramphenicol. Sequencing of inserts of recombinant plasmids was carried out as described previously.6
Susceptibility testing
MICs of selected ß-lactams were determined by the agar dilution technique on MH agar plates as described previously,6 and interpreted according to the NCCLS guidelines.11
Biochemical analysis of CTX-M-15 and CTX-M-3
Cultures of E. coli DH10B with plasmids pCTX-M-15 and pCTX-M-3 were grown overnight at 37°C in 4 L of trypticase soy broth containing ampicillin (100 mg/L) and chloramphenicol (30 mg/L). ß-Lactamase extracts were obtained using purification steps with a Q-Sepharose column, then an S-Sepharose column followed by elution at 50 mM NaCl, as described previously.6 ß-Lactamase-positive fractions were pooled and dialysed against 50 mM phosphate buffer (pH 7), and subsequently concentrated 10-fold with Centrisart-C30 microcentrifuge filters (Sartorius, Goettingen, Germany).6
Analytical isoelectric focusing (IEF) using an ampholine-containing polyacrylamide gel and purity of the enzymes and relative molecular masses estimated by SDS–PAGE analysis were carried out as reported previously.6
Purified ß-lactamases were then used for kinetic measurements at 30°C in 100 mM sodium phosphate buffer (pH 7.0). The initial rates of hydrolysis were determined with an ULTROSPEC 2000 UV spectrophotometer (Amersham Pharmacia Biotech), as described previously.6 The 50% inhibitory concentrations (IC50 values) were determined as reported previously.6 Specific activities of the purified ß-lactamases were evaluated as previously reported; one unit of enzyme activity was defined as the activity that hydrolysed 100 µmol of cefalothin per minute.6
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Results and discussion |
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TopAbstractIntroductionMaterials and methodsResults and discussionReferences |
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Recombinant plasmids and susceptibility testing
The DNA inserts of the two recombinant plasmids pCTX- M-15 and pCTX-M-3 were sequenced, confirming that they contained the blaCTX-M-15 and blaCTX-M-3 genes, respectively. The 3'-end of ISEcp1 was located 48 and 128 bp upstream of the start codon of blaCTX-M-15 and blaCTX-M-3, respectively (data not shown), indicating that the surrounding sequences of these two blaCTX-M genes were different.
E. coli DH10B that harboured pCTX-M-15 and pCTX-M-3 demonstrated a typical inhibitor-susceptible ESBL-mediated resistance profile (Table 1). MICs of ß-lactams for E. coli DH10B (pCTX-M-15) mirrored those for E. coli DH10B (pCTX-M-3) except for ceftazidime; the MIC of ceftazidime for the CTX-M-15 producer was significantly higher than that for the CTX-M-3 producer.
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Biochemical analysis of CTX-M-15 and CTX-M-3
The specific activities of purified ß-lactamases CTX-M-15 and CTX-M-3 were 185 and 138 mU/mg of protein, respectively, with a 50-fold purification factor in both cases. Their purification level was 90% (data not shown). IEF analysis identified pI values for CTX-M-15 and CTX-M-3 of 8.9 and 8.4, respectively. The relative molecular masses of CTX- M-15 and CTX-M-3, determined by SDS–PAGE analysis, were 29 kDa (data not shown).
The glycine residue in position 240 in CTX-M-15 provided lower hydrolytic activity (lower kcat values) for penicillins compared with CTX-M-3, as found for CTX-M-16 and CTX-M-9, which differ by the same amino acid substitution in position 240.6 The overall hydrolytic activity of CTX-M-15 against cephalosporins was not higher than that of CTX-M-3, depending on the cephalosporin molecule.
CTX-M-15 had higher affinities (low Km) than CTX-M-3 for all the ß-lactams studied except for cefepime. This was particularly true for aztreonam, as found for CTX-M-16 when compared with CTX-M-9.3
In general, CTX-M-15 and CTX-M-3 had strong catalytic efficiency (high kcat/Km) against benzylpenicillin, piperacillin, cefotaxime and ceftriaxone (Table 2), as reported for other CTX-M-type enzymes such as CTX-M-16 and CTX-M-18.3,6 The comparison of catalytic efficiencies of CTX- M-15 with those of CTX-M-3 revealed that cefuroxime and benzylpenicillin, respectively, were the best substrates for the two enzymes. The catalytic efficiencies of CTX-M-15 and CTX-3 did not correlate perfectly with the MIC values for E. coli producing CTX-M-15 and CTX-M-3, possibly caused by high copy number (100 copies) of the cloning vector, which may substantially increase the amount of enzymes present in the periplasmic space.
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In the case of ceftazidime, higher MIC values for CTX- M-15 producer than that for CTX-M-3 producer could be explained by different kinetic parameters. CTX-M-15, but not CTX-M-3, demonstrated a detectable, although relatively low, catalytic activity against ceftazidime, along with a low affinity for this substrate (high Km value). Similar observations had previously been reported for the two other ceftazidime-hydrolysing CTX-M-type enzymes, i.e. CTX-M-16 and CTX-M-19.3–5
The kinetic parameters of CTX-M-15 against ceftazidime may be explained by the glycine residue at position 240. This amino acid residue at position 240 is not conserved among class A ß-lactamases.7 Some amino acid residues in this position have been found to play a key role in the extended hydrolytic profile of several ESBLs. Amino acid residue Gly-240 is found in other ESBLs such as VEB-1, BES-1 and PER-1.3,12 Conversely, in a previous study,12 we have reported that the substitution Gly-240Glu in PER-1 caused a reduction in affinity of the enzyme for aztreonam and decreased its catalytic efficiency against cefotaxime and ceftazidime.
CTX-M-15 and CTX-M-3 were similarly prone to inhibition by clavulanic acid (IC50 values 9 and 12 nM, respectively) and by tazobactam (IC50 values 2 and 6 nM, respectively). The relatively higher susceptibility to inhibition by tazobactam compared with clavulanic acid is a feature of CTX-M-type enzymes.1
Data presented in this work indicate further that detection of CTX-M-type ESBLs can no longer be based only on a resistance pattern that includes resistance to cefotaxime and susceptibility to ceftazidime. The role of clinical usage of ceftazidime should be evaluated for selection of novel ceftazidime-hydrolysing CTX-M-type enzymes that may occur through a single amino acid substitution. This is true especially for the CTX-M-1- and CTX-M-9-type ß-lactamases, which are spread worldwide.1–6,8,10
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Acknowledgements |
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This work was funded by a grant from the Ministère de l’Education Nationale et de la Recherche (UPRES-EA), Faculté de Médecine Paris-Sud, Université Paris XI, Paris, France.
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Footnotes |
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* Corresponding author. Tel: +33-1-45-21-36-32; Fax: +33-1-45-21-63-40; E-mail: nordmann.patrice{at}bct.ap-hop-paris.fr
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C. Moubareck, Z. Daoud, N. I. Hakime, M. Hamze, N. Mangeney, H. Matta, J. E. Mokhbat, R. Rohban, D. K. Sarkis, and F. Doucet-Populaire Countrywide Spread of Community- and Hospital-Acquired Extended-Spectrum {beta}-Lactamase (CTX-M-15)-Producing Enterobacteriaceae in Lebanon J. Clin. Microbiol., July 1, 2005; 43(7): 3309 - 3313. [Abstract] [Full Text] [PDF]
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J. Kim, Y.-M. Lim, Y.-S. Jeong, and S.-Y. Seol Occurrence of CTX-M-3, CTX-M-15, CTX-M-14, and CTX-M-9 Extended-Spectrum {beta}-Lactamases in Enterobacteriaceae Clinical Isolates in Korea Antimicrob. Agents Chemother., April 1, 2005; 49(4): 1572 - 1575. [Abstract] [Full Text] [PDF]
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K. J. Welsh, M. Barlow, F. C. Tenover, J. W. Biddle, J. K. Rasheed, L. A. Clark, and J. E. McGowan Jr. Experimental Prediction of the Evolution of Ceftazidime Resistance in the CTX-M-2 Extended-Spectrum Beta-Lactamase Antimicrob. Agents Chemother., March 1, 2005; 49(3): 1242 - 1244. [Abstract] [Full Text] [PDF]
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C. Moubareck, F. Doucet-Populaire, M. Hamze, Z. Daoud, and F.-X. Weill First Extended-Spectrum-{beta}-Lactamase (CTX-M-15)-Producing Salmonella enterica Serotype Typhimurium Isolate Identified in Lebanon Antimicrob. Agents Chemother., February 1, 2005; 49(2): 864 - 865. [Full Text] [PDF]
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J. Gangoue-Pieboji, V. Miriagou, S. Vourli, E. Tzelepi, P. Ngassam, and L. S. Tzouvelekis Emergence of CTX-M-15-Producing Enterobacteria in Cameroon and Characterization of a blaCTX-M-15-Carrying Element Antimicrob. Agents Chemother., January 1, 2005; 49(1): 441 - 443. [Abstract] [Full Text] [PDF]
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L. Poirel, M.-F. Lartigue, J.-W. Decousser, and P. Nordmann ISEcp1B-Mediated Transposition of blaCTX-M in Escherichia coli Antimicrob. Agents Chemother., January 1, 2005; 49(1): 447 - 450. [Abstract] [Full Text] [PDF]
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T. Conceicao, A. Brizio, A. Duarte, L. M. Lito, J. M. Cristino, and M. J. Salgado First Description of CTX-M-15-Producing Klebsiella pneumoniae in Portugal Antimicrob. Agents Chemother., January 1, 2005; 49(1): 477 - 478. [Full Text] [PDF]
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 Y.-R. Kim, S.-I. Kim, J.-Y. Lee, Y.-J. Park, K.-Y. Lee, and M.-W. Kang NosocomialTransmission of CTX-M-15 and OXA-30 {beta}-Lactamase-Producing Escherichia coli in a Neurosurgical Intensive Care Unit Ann. Clin. Lab. Sci., January 1, 2005; 35(3): 297 - 301. [Abstract] [Full Text] [PDF]
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C. J. Munday, D. A. Boyd, N. Brenwald, M. Miller, J. M. Andrews, R. Wise, M. R. Mulvey, and P. M. Hawkey Molecular and Kinetic Comparison of the Novel Extended-Spectrum {beta}-Lactamases CTX-M-25 and CTX-M-26 Antimicrob. Agents Chemother., December 1, 2004; 48(12): 4829 - 4834. [Abstract] [Full Text] [PDF]
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J. D. D. Pitout, A. Hossain, and N. D. Hanson Phenotypic and Molecular Detection of CTX-M-{beta}-Lactamases Produced by Escherichia coli and Klebsiella spp. J. Clin. Microbiol., December 1, 2004; 42(12): 5715 - 5721. [Abstract] [Full Text] [PDF]
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V. Leflon-Guibout, C. Jurand, S. Bonacorsi, F. Espinasse, M. C. Guelfi, F. Duportail, B. Heym, E. Bingen, and M.-H. Nicolas-Chanoine Emergence and Spread of Three Clonally Related Virulent Isolates of CTX-M-15-Producing Escherichia coli with Variable Resistance to Aminoglycosides and Tetracycline in a French Geriatric Hospital Antimicrob. Agents Chemother., October 1, 2004; 48(10): 3736 - 3742. [Abstract] [Full Text] [PDF]
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D. A. Boyd, S. Tyler, S. Christianson, A. McGeer, M. P. Muller, B. M. Willey, E. Bryce, M. Gardam, P. Nordmann, and M. R. Mulvey Complete Nucleotide Sequence of a 92-Kilobase Plasmid Harboring the CTX-M-15 Extended-Spectrum Beta-Lactamase Involved in an Outbreak in Long-Term-Care Facilities in Toronto, Canada Antimicrob. Agents Chemother., October 1, 2004; 48(10): 3758 - 3764. [Abstract] [Full Text] [PDF]
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E. Liebana, M. Batchelor, C. Torres, L. Brinas, L. A. Lagos, B. Abdalhamid, N. D. Hanson, and J. Martinez-Urtaza Pediatric Infection Due to Multiresistant Salmonella enterica Serotype Infantis in Honduras J. Clin. Microbiol., October 1, 2004; 42(10): 4885 - 4888. [Abstract] [Full Text] [PDF]
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N. Woodford, M. E. Ward, M. E. Kaufmann, J. Turton, E. J. Fagan, D. James, A. P. Johnson, R. Pike, M. Warner, T. Cheasty, et al. Community and hospital spread of Escherichia coli producing CTX-M extended-spectrum {beta}-lactamases in the UK J. Antimicrob. Chemother., October 1, 2004; 54(4): 735 - 743. [Abstract] [Full Text] [PDF]
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M. Cartelle, M. del Mar Tomas, F. Molina, R. Moure, R. Villanueva, and G. Bou High-Level Resistance to Ceftazidime Conferred by a Novel Enzyme, CTX-M-32, Derived from CTX-M-1 through a Single Asp240-Gly Substitution Antimicrob. Agents Chemother., June 1, 2004; 48(6): 2308 - 2313. [Abstract] [Full Text] [PDF]
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S. Kimura, M. Ishiguro, Y. Ishii, J. Alba, and K. Yamaguchi Role of a Mutation at Position 167 of CTX-M-19 in Ceftazidime Hydrolysis Antimicrob. Agents Chemother., May 1, 2004; 48(5): 1454 - 1460. [Abstract] [Full Text] [PDF]
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R. Bonnet Growing Group of Extended-Spectrum {beta}-Lactamases: the CTX-M Enzymes Antimicrob. Agents Chemother., January 1, 2004; 48(1): 1 - 14. [Full Text] [PDF]
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W.-L. Yu, K.-C. Cheng, L.-T. Wu, M. A. Pfaller, P. L. Winokur, and R. N. Jones Emergence of Two Klebsiella pneumoniae Isolates Harboring Plasmid-Mediated CTX-M-15 {beta}-Lactamase in Taiwan Antimicrob. Agents Chemother., January 1, 2004; 48(1): 362 - 363. [Full Text] [PDF]
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L. Pagani, E. Dell'Amico, R. Migliavacca, M. M. D'Andrea, E. Giacobone, G. Amicosante, E. Romero, and G. M. Rossolini Multiple CTX-M-Type Extended-Spectrum {beta}-Lactamases in Nosocomial Isolates of Enterobacteriaceae from a Hospital in Northern Italy J. Clin. Microbiol., September 1, 2003; 41(9): 4264 - 4269. [Abstract] [Full Text] [PDF]
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S. Mushtaq, N. Woodford, N. Potz, and D. M. Livermore Detection of CTX-M-15 extended-spectrum {beta}-lactamase in the United Kingdom J. Antimicrob. Chemother., September 1, 2003; 52(3): 528 - 529. [Full Text] [PDF]
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