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Antimicrobial Agents and Chemotherapy, September 2000, p. 2549-2553, Vol. 44, No. 9
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Molecular Characterization of FOX-4, a New
AmpC-Type Plasmid-Mediated 
-Lactamase from an Escherichia
coli Strain Isolated in Spain
Germán
Bou,1,
Antonio
Oliver,1
Mar
Ojeda,2
Carmelo
Monzón,2 and
Jesús
Martínez-Beltrán1,*
Servicio de Microbiología, Hospital
Ramón y Cajal, 28034 Madrid,1 and
Servicio de Microbiología, Hospital Insular, Las
Palmas de Gran Canaria,2 Spain
Received 8 October 1999/Returned for modification 28 February
2000/Accepted 9 June 2000
 |
ABSTRACT |
A clinical strain of Escherichia coli (Ec GCE)
displayed resistance to cefoxitin, cefotetan, cefotaxime, and
ceftazidime. Susceptibility was not restored by the addition of
clavulanic acid. Two 
-lactamases with apparent pIs of 5.4 and 6.4 were identified; the -lactamase with a pI of 6.4 was transferred by
conjugation and associated with a 40-kb plasmid. Analysis of the
nucleotide sequence showed a new ampC -lactamase gene
that is closely related to those encoding the FOX-3, FOX-2, and FOX-1
-lactamases but whose product has four novel amino acid mutations,
at positions 11 (M
T), 43 (AE), 233 (VA), and 280 (YH). This
first cephamycinase from Spain was named FOX-4.
| |
TEXT |
Plasmid-mediated class A
-lactamases derived from the commonly found TEM and SHV enzymes have
been extensively reported (9, 10). They confer resistance to
extended-spectrum cephalosporins and aztreonam, but cephamycins are
unaffected. The enzymes remain susceptible to inhibition with the
addition of clavulanic acid.
Plasmid-mediated class C -lactamases have been reported in the last
decade for Klebsiella pneumoniae, Escherichia
coli, Salmonella spp., and Proteus spp.
(2, 3, 4, 7, 14, 24). These -lactamases show sequence
similarities to AmpC -lactamases (1) of
Enterobacter cloacae (ACT-1 and MIR-1), Citrobacter
freundii (CMY-2, BIL-1, LAT-2, and LAT-1), and Pseudomonas
aeruginosa (CMY-1, FOX-1, and MOX-1) and confer a similar
resistance pattern to that of AmpC chromosomally mediated enzymes
(8).
An E. coli strain (Ec GCE) that is resistant to a broad
spectrum of -lactam antibiotics, including cephamycins, was isolated recently at Hospital Insular in Las Palmas de Gran Canaria (Canary Islands, Spain) from a patient suffering from a urinary tract infection
who was previously treated with cloxacillin, aztreonam, and cefotaxime
for an abdominal surgical infection. Our results showed that this
strain harbored a new plasmid-encoded cephamycin-hydrolyzing -lactamase, the first plasmid-mediated cephamycinase isolated in Spain.
Susceptibility to -lactams.
Antibiotic susceptibility
patterns of the Ec GCE clinical strain, as well as its transconjugant
and transformant, are shown in Table 1.
MICs were determined by the agar dilution method as recommended by the
National Committee for Clinical Laboratory Standards (18).
Antibiotics were provided as powders by the corresponding
manufacturers.
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TABLE 1.
MICs of -lactams for the Ec GCE clinical strain,
E. coli MC4100(pGC1), E. coli TG1, and
E. coli TG1(pGC-2)
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|
Clavulanic acid did not act synergistically with ampicillin and
cephalosporins on E. coli MC4100 and TG1 strains harboring pGC-1 and pGC-2 plasmids, respectively. A slight synergistic effect was
observed only with ampicillin for the clinical strain Ec GCE, which
produced a TEM-1 enzyme in addition to the AmpC -lactamase. In
addition, high levels of resistance to cefoxitin and cefotetan were
observed, together with a moderate level of resistance to moxalactam.
Higher MICs were obtained with the E. coli TG1 transformant harboring the pGC-2 plasmid, probably due to more copies of the ampC gene.
Isoelectric focusing.
Isoelectric focusing was performed in
polyacrylamide gels containing Ampholine with a pH range of 3.5 to 9.5, as previously described (17). The clinical isolate produced
two enzymes, one with a pI of 5.4 (TEM-1 type) and one with a pI of 6.4 (AmpC type).
Conjugation experiments.
In this study the E. coli
MC4100 strain, with nalidixic acid and kanamycin resistances for
markers, was used in the conjugation experiments and E. coli
TG1 was used as the host for cloning the ampC gene. Plasmid
pBGS18
(23), with a kanamycin resistance
marker, was used for cloning the -lactamase gene.
The Ec GCE clinical strain had two plasmids. Plasmid DNA from Ec GCE,
which harbored the -lactamase with a pI of 6.4, was transferred by
conjugation into E. coli MC4100, with kanamycin (256 µg/ml), nalidixic acid (50 µg/ml), and ceftazidime (16 µg/ml) as
selector antibiotics. A few transconjugants grew which harbored an
identical plasmid of approximately 40 kb, named pGC-1. The other
plasmid from the Ec GCE clinical strain carried the
blaTEM-1 gene and would probably be transferred
if an appropriate antibiotic (i.e., ampicillin) was used for selection.
The presence of the blaTEM-1 gene in the Ec GCE
strain was demonstrated by PCR assay with specific
blaTEM primers C1
(5'-GGGAATTCTCGGGGAAATGTGCGCGGAAC) and C2
(5'-GGGATCCGAGTAAACTTGGTCTGACAG).
Cloning experiments and nucleotide sequencing.
Plasmid DNA was
isolated by the alkaline lysis method (21) from the
ceftazidime-resistant transconjugant that produced a single
-lactamase with a pI of 6.4. Plasmid DNA was digested with
HindIII, and the resulting fragments were ligated to the plasmid pBGS18; which was previously digested with the same restriction enzyme. The ligation mixture was introduced into E. coli TG1 by transformation with CaCl2, and
transformants were detected on Luria-Bertani agar plates supplemented
with ceftazidime (4 µg/ml) and kanamycin (50 µg/ml). The resultant
plasmid carrying the bla gene was named pGC-2. The molecular
size of the insert was estimated by using restriction enzymes and
electrophoresis on 1% agarose gels.
Double-stranded templates were subjected to nucleotide sequencing by
the method of Sanger et al. (22). Sequencing was carried out
with the Taq DyeDeoxiTerminator cycle sequencing kit and
specific primers to the coding sequence, and the sequence was analyzed in an automatic DNA sequencer (377 Abi-Prism; Perkin-Elmer).
Several transformants harbored the recombinant pGC-2 plasmid, with an
insert of about 3.3 kb. In isoelectric focusing, the pI 6.4 -lactamase activity band from the E. coli transformant cofocused with the -lactamase activity band from the Ec GCE clinical strain. Nucleotide sequencing of the 3.3 kb insert (Fig.
1) revealed, in
addition to a new bla gene, the presence
of ORF341 and a conserved integron sequence previously
identified in the In7 integron (2, 19). This new
bla gene was 1,149 bp long (Fig. 1), initiated with an ATG
codon, and ended with a TGA codon (382 amino acids long). The
initiation codon was preceded by a Shine-Dalgarno ribosome-binding sequence, GAGAA, and putative 
10 and 35 promoter regions,
TTTATA and TTCGGAT, respectively. EMBL and SwissProt database
searches for this open reading frame revealed similarities with several class C chromosome- and plasmid-mediated -lactamases. The new protein had the greatest homology with FOX-2, FOX-3, and FOX-1 -lactamases (97.4, 96.9, and 95.3% homology), AER14 and CEPS -lactamases (20, 25) from Aeromonas sobria (76 and 74% homology), and to a lesser extent, CMY-1 (5), MOX-1
(13), and AmpC from P. aeruginosa (73 to 55%
homology) (15) and AmpC (6) from Acinetobacter baumannii (41.6% homology).
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FIG. 1.
Nucleotide sequence of the 3.3-kb fragment. The
deduced amino acid sequence of FOX-4 -lactamase is shown in the line
below the nucleotide triplets. The boldface ATG and TGA represent the
initiation and termination codons, respectively. A putative
Shine-Dalgarno (S.D.) ribosomal recognition site and 10 and 35
consensus sequences are indicated. The positions of the primers used to
sequence the gene are indicated by arrows. The -lactamase active
site SVSK, the conserved triad KTG, and the typical class C motif YXN
are presented in boldface. Nucleotides 1 to 64 and 2353 to 3319 correspond to ORF341, previously identified in the In7
integron. Nucleotides 65 to 808 and 2059 to 2352 correspond to a
conserved region in the same In7 integron (EMBL database accession no.
L06418).
|
|
Multiple alignment was calculated with the Clustal V program
(12). Figure 2 shows the amino
acid replacements between FOX -lactamases. In FOX-4, there are four
novel mutations, at positions 11 (MT), 43 (AE), 233 (VA), and
280 (YH). The other FOX-4 amino acid changes are found in positions
previously described for FOX-2 and FOX-3 -lactamases, although in
some positions the amino acid changes were different from those
previously reported.
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FIG. 2.
Amino acid sequences of the FOX enzymes. Amino acid
replacements are indicated. The -lactamase active site SVSK, the
conserved triad KTG, and the typical class C motif YXN are presented in
boldface.
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|
Determination of the -lactamase kinetic constants
Km, Vmax, and
hydrolysis rate.
The substrate profile of the -lactamase was
determined with enzyme that was partially purified by G100 Sephadex
(Pharmacia Fine Chemicals AB, Uppsala, Sweden), as previously described
(6). Initial hydrolysis rates were monitored
spectrophotometrically (UVIKON-930) at 25°C in 0.05 M phosphate
buffer (pH 7.4) (14). Kinetic parameters were determined in
duplicate experiments based on the initial steady-state rates at
different substrate concentrations (Lineweaver-Burk transformation).
FOX-4 showed a hydrolytic profile similar to that expected for a class
C molecular cephalosporinase (Table 2).
The enzyme hydrolyzed cephaloridine with a Vmax
500-fold higher than that for ampicillin and only 30-fold higher than
that for cefoxitin. This enzyme also showed moderate hydrolytic
activity against cefotaxime, ceftazidime, and cefepime and very little
hydrolytic activity against moxalactam and imipenem. A low
Km value for cefotaxime (1.23 µM) was
responsible for a high hydrolytic efficiency
(Vmax/Km) for this
antibiotic which was approximately equal to that of cephaloridine. Interestingly, a very high hydrolytic efficiency was obtained with
cefoxitin, which is similar to results obtained with the FOX-1
-lactamase (14). The hydrolysis rates for moxalactam and
imipenem were very low, thus preventing the determination of reliable
Km and Vmax values.
Comparative studies.
In recent years, ampC genes
have been found in conjugative plasmids, mostly among K. pneumoniae and E. coli strains but also in
Klebsiella oxytoca, Salmonella enterica serovar
Enteritidis, and Proteus mirabilis (2, 3, 4, 7, 14,
24). The nucleotide and deduced amino acid sequences of the
-lactamase characterized here had very close homology with FOX-1,
FOX-2, and FOX-3 -lactamases (4, 14, 16). Moreover, the
deduced peptide sequence of blaFOX-4 contained
the common conserved motifs found in serine -lactamases
(11): the SXSK motif of the active site of AmpC, the typical
class C motif YXN, and the KTG domain. In addition, kinetic experiments
performed with the semipurified enzyme revealed typical
cephalosporinase properties, especially a high hydrolytic efficiency of
the enzyme for cefoxitin and cefotaxime. These biochemical results
correlated well with the MICs of -lactams for the clinical strain
and its transconjugant and transformant. A high cefoxitin hydrolytic
efficiency was also observed with the FOX-1 -lactamase.
On the other hand, FOX-4 -lactamase and all the FOX enzymes had the
greatest homology to the ampC genes from A. sobria; therefore, the ampC -lactamase genes from
A. sobria may be ancestors of the FOX genes.
However, it is possible that other ampC genes, from
Enterobacteriaceae and other gram-negative rods, which have not yet been sequenced, may assume this role.
Recently, two new blaFOX genes have been
identified (N. D. Hanson, P. Coudron, E. S. Moland, and
C. C. Sanders, Abstr. 39th Intersci. Conf. Antimicrob. Agents
Chemother., abstr. 1458, 1999; G. Jacoby, J. Tran, and M. Nato, Abstr.
39th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 1481, 1999).
Since we do not have enough experimental data to compare them, we named
our enzyme FOX-4.
In summary, we report here the molecular characterization of a novel
-lactamase, FOX-4, from an E. coli clinical strain. To
our knowledge, this is the first report of a cephamycinase in Spain.
Nucleotide sequence accession number.
The nucleotide sequence
of the blaFOX-4 gene has been given the EMBL
database accession no. AJ277535.
| |
ACKNOWLEDGMENTS |
We thank L. De Rafael for his critical comments, Dolores Malpica
for technical assistance, and Reyes Garcia for secretarial assistance.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Servicio de
Microbiología, Hospital Ramón y Cajal, Carretera Colmenar
Viejo km. 9.100, 28034 Madrid, Spain. Phone: (91) 3368082. Fax: (91)
3368809. E-mail: jmtzbeltran{at}hrc.insalud.es.
Present address: Department of Immunology, Mayo Clinic,
Rochester, MN 55905.
| |
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Antimicrobial Agents and Chemotherapy, September 2000, p. 2549-2553, Vol. 44, No. 9
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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