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Antimicrobial Agents and Chemotherapy, August 1999, p. 1924-1931, Vol. 43, No. 8
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
A Novel Type of AmpC 
-Lactamase, ACC-1, Produced
by a Klebsiella pneumoniae Strain Causing Nosocomial
Pneumonia
Adolf
Bauernfeind,1,*
Ines
Schneider,1
Renate
Jungwirth,1
Hany
Sahly,2 and
Uwe
Ullmann2
Max von Pettenkofer Institute,
Munich,1 and Institute for Medical
Microbiology and Virology, Kiel,2 Federal
Republic of Germany
Received 16 October 1998/Returned for modification 15 February
1999/Accepted 7 June 1999
 |
ABSTRACT |
A Klebsiella pneumoniae strain resistant to oxyimino
cephalosporins was cultured from respiratory secretions of a patient suffering from nosocomial pneumonia in Kiel, Germany, in 1997. The
isolate harbors a bla resistance gene located on a
transmissible plasmid. An Escherichia coli transconjugant
produces a 
-lactamase with an isoelectric point of 7.7 and a resistance phenotype characteristic of an AmpC (class 1)
-lactamase except for low MICs of cephamycins. The
bla gene was cloned and sequenced. It encodes a protein of 386 amino acids with the active site serine of the S-X-X-K motif at
position 64, as is characteristic for class C
-lactamases. Multiple alignment of the deduced amino
acid sequence with 21 other AmpC -lactamases
demonstrates only very distant homology, reaching at maximum 52.3%
identity for the chromosomal AmpC -lactamase of
Serratia marcescens SR50. The -lactamase of
K. pneumoniae KUS represents a new type of AmpC-class
enzyme, for which we propose the designation ACC-1 (Ambler class C-1).
| |
INTRODUCTION |
Resistance of bacterial pathogens to
-lactam antibiotics is frequently mediated by
-lactamases. bla genes located on
transmissible plasmids have been observed for Ambler class A
-lactamases since 1963 (TEM-1 [15]). In
contrast, bla genes coding for class C -lactamases (class 1 in the classification by Bush et
al. [12]) are primarily chromosomally located.
Plasmid-borne transmissible ampC genes were first discovered
about 25 years after the plasmidic class A bla genes (MIR-1
in 1988 [32] and CMY-1 in 1989 [4]). Since then, plasmid-borne ampC genes have been detected in
many regions of the world (2, 6, 8, 10, 11, 16, 18, 19, 22, 27,
37, 38). They contribute to the spread of multidrug resistant
Klebsiella pneumoniae, Escherichia coli, and other Enterobacteriaceae.
We report the first plasmid-encoded AmpC-type -lactamase
originating in Germany (Kiel, Schleswig-Holstein, 1997). The gene designated blaACC-1 (Ambler class C) has a
unique nucleotide sequence with only distant homology of its deduced
amino acid sequence with known AmpC -lactamases and an
unusual resistance phenotype due to its low activity against
cephamycins. It therefore presents a new and so far solitary type among
the AmpC -lactamases.
(Part of this work was presented at the 38th Interscience Conference on
Antimicrobial Agents and Chemotherapy, San Diego, Calif., 24 to 27 September 1998.)
| |
MATERIALS AND METHODS |
Case history. (i) Clinical background.
K. pneumoniae
KUS was isolated in 1997 from a 31-year-old male patient. The patient
was diabetic and had been admitted to the Kiel University Hospital
because of convulsive seizures due to hypo-osmolaric coma. He developed
multiple pulmonary complications that necessitated mechanical
ventilation for a total of 8 weeks. After 3 months of hospitalization,
the patient had recovered and was transferred to a rehabilitation center.
(ii) Bacteriological findings and antibiotic therapy.
Early
onset pneumonia was caused by Streptococcus pneumoniae,
which was eradicated by therapy with tazobactam. Consecutively, a
late-onset pneumonia caused by K. pneumoniae was treated by combined antibiotic therapy of imipenem plus ciprofloxacin for 3 weeks.
As K. pneumoniae was not eradicated, therapy was changed to
meropenem plus ciprofloxacin and continued for another 20 days. Although K. pneumoniae persisted in throat and skin
cultures, antibiotic treatment was discontinued as signs and symptoms
of inflammation were no longer diagnosed.
Bacterial strains and vectors.
Strains and vectors used in
this study are characterized in Table 1.
Antibiotics.
The following antibiotics were obtained from
the indicated manufacturers: ceftazidime (Cascan GmbH & Co. KG,
Wiesbaden, Germany); cefotaxime, cefpirome, and tetracycline
(Hoechst AG, Frankfurt on the Main, Germany); clavulanate and BRL 42715 (SmithKline Beecham Pharmaceuticals, London, United Kingdom); sulbactam
(Pfizer, Karlsruhe, Germany); tazobactam (Lederle, Münster,
Germany); cefepime and aztreonam (Bristol-Myers Squibb, Munich,
Germany); cefoxitin and imipenem (Merck Sharp & Dohme, Munich,
Germany); cefoteten and meropenem (Zeneca GmbH, Plankstadt, Germany);
Ro 47-8284, sulfamethoxazole, and trimethoprim (Hoffmann-La Roche Inc.,
Basel, Switzerland); moxalactam and tobramycin (Lilly Deutschland GmbH,
Bad Homburg, Germany); flomoxef (Shionogi, Düsseldorf, Germany);
and chloramphenicol (Boehringer, Mannheim, Germany). Combinations of
ceftazidime or cefotetan with -lactamase inhibitors were
used at the following proportions: clavulanate, 1/4; sulbactam, 1/2;
tazobactam, 1/8; and BRL 42715 (14) and Ro 47-8284 (53) at a constant concentration of 4 µg/ml.
Susceptibility testing.
For determination of MICs, a
standard procedure described by the National Committee for Clinical
Laboratory Standards was followed (29). E. coli
ATCC 25922 was used as the MIC reference strain.
Transfer of resistance determinants.
The procedure for
conjugation experiments was described previously (8).
Transconjugants were selected on MacConkey agar (Unipath GmbH,
Wesel, Germany) supplemented with rifampin (128 µg/ml) and
ceftazidime (2 µg/ml).
Inducibility of the synthesis of ACC-1.
Inducibility of
ACC-1 production was tested by a double disk test with cefoxitin as the
inducing compound. An Enterobacter cloacae strain
producing an inducible AmpC -lactamase was used as a reference.
Identification of the isoelectric point (pI) of ACC-1.
Sonicates of strains were prepared as described previously
(5). For isoelectric focusing of their
-lactamases, the procedure of Matthew et al.
(28) was modified (5). After isoelectric focusing, the polyacrylamide gel was covered by a 0.75% tryptic soy
agar (TSA) (Difco, Augsburg, Germany) overlay containing the -lactam
to be tested for inactivation and incubated for 2 h at 35°C. A
second TSA layer with a strain (1.2 × 107 CFU/ml)
susceptible to the -lactam used was then applied. After overnight
incubation at 35°C, growth of the indicator strain on the gel
identifies the position at which the -lactam had been inactivated.
Kinetic analysis of the ACC-1 -lactamase.
The
ACC-1 -lactamase for the kinetic analysis was obtained
from the transformant strain MV1190 T+. Bacteria from a
1-liter overnight culture of tryptic soy broth (TSB) supplemented with
100 µg of ampicillin/ml were harvested by centrifugation and washed
with 50 mM phosphate buffer (pH 7.0). The pellet was resuspended in 2 ml of 0.2 M sodium acetate, and subjected to five freeze-thaw cycles.
ACC-1 was partially purified by Sephadex G-100 chromatography in 50 mM
phosphate buffer (pH 7.0). Fractions containing nitrocefin-hydrolyzing
activity were precipitated with 90% ammonium sulfate; pellets were
resuspended in 50 mM phosphate buffer (pH 7.0) and dialyzed in the same
buffer overnight at 4°C. Initial hydrolysis rates were measured on a Shimadzu UV-1601 spectrophotometer at 25°C in 50 mM phosphate buffer
(pH 7.0). Km and Vmax
values were obtained by using Lineweaver-Burk, Eadie-Hofstee,
Hanes-Woolf, and direct linear plot analyses. Substrates were assayed
on at least two separate days, with cephaloridine included as a
reference each day. Due to the slow hydrolysis rate detected with
ceftazidime, a Ki value was determined:
cephaloridine was used as the substrate and ceftazidime was used as the
competing substrate following a 5-min preincubation of enzyme with
ceftazidime to establish a steady state.
Plasmid DNA preparation.
Cells were grown overnight in 150 ml of TSB (Oxoid, Wesel, Germany) supplemented with ceftazidime (1 µg/ml). DNA preparation was performed by alkaline lysis
(9). Plasmid DNA in the lysate was purified with an anion
exchange column (tip 100; Qiagen, Hilden, Germany) according to the
recommendations of the manufacturer.
Cloning and sequencing of the blaACC-1
gene.
Cloning experiments were performed by following standard
procedures (35). The plasmid DNA of an E. coli
transconjugant strain carrying the blaACC-1 gene
was partially digested with SauIIIa and subsequently ligated
into vector pBC. DNA fragments were purified with the QIAquick
purification kit (Qiagen). For ligation, vector and insert DNA were
mixed in ratios of 1:3 and 1:6. Ligation buffer and 1 U of T4 ligase
were added, and the mixture was incubated at 16°C overnight. The
ligase was then inactivated at 70°C for 10 min. Cells of E. coli MV1190 were transformed by electroporation. Transformants
were selected on TSA containing 2 µg of ceftazidime/ml, 20 µg of
X-Gal
(5-bromo-4-chloro-3-indolyl--D-galactopyranoside)/ml, and 0.5 mM IPTG (isopropyl--D-thiogalactopyranoside).
After overnight incubation at 37°C, white colonies were isolated and
screened for inserts in vector pBC. From two transformants, inserts of 2.0 or 2.3 kb were sequenced. Sequencing was performed with consecutive primers by the dideoxy chain termination procedure of Sanger
(36) with an automatic sequencer (model 373A; Applied
Biosystems, Weiterstadt, Germany).
Sequence analysis.
-Lactamase relatedness was
investigated by comparison with EMBL and Swissprot databases (Fasta).
Multiple alignment was calculated with Clustal V (20, 21).
Nucleotide sequence accession number.
The nucleotide
sequence data reported in this paper will appear in the EMBL database
under accession no. AJ133121.
| |
RESULTS |
Phenotypic characterization of the ACC-1
-lactamase of K. pneumoniae KUS.
The blaACC-1 gene was conjugated into an
E. coli recipient strain together with the
blaTEM-1 gene. The expression of the
blaACC-1 gene in transconjugant and transformant
strains significantly increased the MICs (equal to or above fourfold)
of a variety of different -lactam structures, namely oxyimino
cephalosporins (ceftazidime and cefotaxime, 64- to 128-fold),
7-methoxy-cephalosporins (cefotetan, moxalactam, and flomoxef, four- to
eightfold), dipolar cephalosporins (cefepime and cefpirome, four- to
eightfold), the monobactam aztreonam (eightfold), and piperacillin
(512-fold in the transconjugant, 64-fold in the transformant). No
increase of MICs by acquisition of the
blaACC-1 gene was detectable against cefoxitin, the 6-methoxy-penicillin temocillin, and the carbapenems (Table 2). MICs of transformants were
reduced only by -lactamase inhibitors active against
class C -lactamases (BRL 42715 [14], Ro
47-8284 [33], 8- to 32-fold). Tazobactam reduced the
MICs of piperacillin of the wild type and the transconjugant strains but not of the transformant strain, as blaTEM-1
was not cloned into the transformant. Inducibility of ACC-1 synthesis
could not be demonstrated by a double-disk test, in which AmpC
production of an Enterobacter cloacae was induced by
cefoxitin (Fig. 1).
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TABLE 2.
Antibiotic susceptibilities of the wild-type K. pneumoniae KUS, the transconjugant E. coli C600
R+, the transformant E. coli MV1190
T+, and the recipient E. coli
C600 R
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FIG. 1.
Double-disk test to check inducibility of ACC-1
synthesis. (a) Inducibility test with K. pneumoniae KUS. (b)
Inducibility test with Enterobacter cloacae WG7250.
Disks: 1, cefoxitin; 2, ceftazidime; 3, cefotaxime; 4, cefotetan;
5, aztreonam.
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Isoelectric focusing of crude homogenates demonstrated two bands at pIs
of 5.4 and 7.7 for the
K. pneumoniae KUS wild type
and the
transconjugant strain and only one band at 7.7 for the
transformant
strain (Fig.
2A). Ceftazidime, cefotetan,
and cefoxitin
were inactivated only at the pI 7.7 band as demonstrated
by growth
of the susceptible indicator strain (Fig.
2B) at this
position.
So the hydrolytic activity of the
-lactamase
ACC-1 was assigned
to the band focusing at pI 7.7.
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FIG. 2.
Isoelectric focusing of -lactamase ACC-1.
The ACC-1 producing wild-type, transconjugant, and transformant strains
revealed a band at a pI lower than 7.8 (SHV-4) but slightly above 7.6 (SHV-2), at about 7.7 (a). This band was able to inactivate
ceftazidime, as shown by a bioassay (b). Lanes for panel a: A,
K. pneumoniae KUS producing ACC-1; B, E. coli C600 R+ producing ACC-1; C, E. coli
DH5 T+ producing ACC-1; D, E. coli
R+ producing SHV-2. Lanes for panel b: A, E. coli R+ producing SHV-4; B, E. coli
R+ producing SHV-2; C, K. pneumoniae KUS
producing ACC-1; D, E. coli C600 R+ producing
ACC-1; E, E. coli DH5 T+ producing ACC-1.
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Kinetic data of the ACC-1 -lactamase.
Measurable hydrolysis rates were not observed for cephalosporins except
for cephaloridine and nitrocefin; however, in a competitive assay, slow
hydrolysis of ceftazidime was detectable (Table
3).
Characterization of the blaACC-1
gene.
A 2,263-bp DNA fragment excised from plasmid DNA of a
transconjugant strain was cloned into E. coli MV1190 (pBC)
and sequenced. An open reading frame of 1,161 nucleotides encoding a
protein of 386 amino acids could be identified (Fig.
3). The deduced amino acid sequence
carries the catalytic residues S-X-X-K (here
serine-leucine-serine-lysine) with the initial serine at position 64 as
is typical of class C -lactamases, the motif Y-S-N
(tryptophan-serine-asparagine) at position 150, and the K-T-G
(lysine-threonine-glycine) motif at position 315. In the 639-bp
nucleotide sequence upstream of the start codon no ampR
motif could be detected. This finding is concordant with the
noninducibility of ACC-1 -lactamase synthesis.
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FIG. 3.
Nucleotide sequence of the
blaACC-1 gene (pMVP-8). The deduced amino acid
sequence of ACC-1 is shown in the line below the nucleotide triplets.
Amino acids of the signal peptide are written in small letters. The
-lactamase active site S-L-S-K, the conserved triad
K-T-G, and the class C-typical motif Y-X-N are underlined. The putative
 10 and 35 promoter regions upstream of the start codon are
underlined. The asterisk indicates the stop codon.
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The deduced amino acid sequence of the enzyme was compared with that of
other chromosomal or plasmid-encoded AmpC
-lactamases.
The percentage of amino acid identity was below 50% for all
-lactamases
included except for the chromosomal
Serratia marcescens SR50 AmpC
-lactamase
(
31) with 52.3% (Table
4).
Multiple alignment of
the amino acid sequence of AmpC
-lactamases demonstrates enzyme-specific
amino acid
fingerprints as well as amino acid positions conserved
in all enzymes
(Fig.
4).
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FIG. 4.
Multiple alignment of amino acid sequences of the
chromosomal AmpC -lactamase of S. marcescens
(32), CMY-2 (6), FOX-2 (8), and ACC-1
(this study).
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DISCUSSION |
The majority of the plasmid-borne ampC genes have been
described in K. pneumoniae (6, 7, 10, 11, 18, 19, 22, 23, 37). Many among them have close homology with chromosomal AmpC -lactamases, e.g., of Citrobacter
freundii (6, 18, 37), or Enterobacter
cloacae (11, 23). So K. pneumoniae may have
acquired these genes from other species at sites where K. pneumoniae lives close to the ecological neighborhood of
ampC-carrying organisms, e.g., other
Enterobacteriaceae, namely in the intestine. The
degree of homology between some of the chromosomal and the plasmid-encoded -lactamases appears to be high
enough to assume a phylogenetic lineage. There remain, however,
both chromosomal and plasmid-mediated AmpC enzymes without a
currently identified counterpart, e.g., the chromosomal
-lactamase of Pseudomonas aeruginosa
(26) or the plasmid-encoded -lactamases
forming the CMY-1 cluster (Fig. 5).
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FIG. 5.
Dendrogram for 22 AmpC (group 1)
-lactamases (calculated by Clustal V using the
neighbor-joining method of Saitou and Nei [34]).
According to the identity of their amino acid sequences with CMY-2, the
group 1 -lactamases might be subclassified into 1a to
1i.
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The enzyme described here as well is highly dissimilar to known AmpC
-lactamases (Table 4, Fig. 5). The closest amino acid sequence homology of the mature enzyme is with the chromosomal AmpC
-lactamase of S. marcescens (31).
The degree of homology is very low (52.3%). There are altogether 181 amino acid substitutions between both enzymes (92 conservative, 89 nonconservative). Thus, the phylogenetic relationship of this enzyme to
others remains unclear. The phenotypic characteristics of the
-lactamase (antibiotic susceptibilities and pI) as well
indicate a distinct type of AmpC -lactamase. In
particular, the resistance phenotype expressed by
blaACC-1-carrying strains is unusual among
AmpC-type -lactamases, as cefoxitin appears to be a poor
substrate. The MIC of cefoxitin for transformants is elevated by a
factor of only two, in comparison with a 64- to 128-fold increase for
transformants producing CMY-1 (4), CMY-2 (6),
FOX-2 (8), or ACT-1 (11). Accordingly, inactivation of cefoxitin as determined in the bioassay is lower in
comparison with ceftazidime. To obtain an equivalent effect, the same
homogenate has to be used undiluted (for cefoxitin) or at a dilution of
1:32 (for ceftazidime), indicating a good correlation between MICs and
the inactivation of these substrates. This reaction proceeds at a
rather low rate, while the affinity for binding appears to be
high. Slow hydrolysis of cephamycins and third generation cephalosporins has been observed for chromosomal cephalosporinases (30).
The low inactivation level of cefoxitin by ACC-1 stimulates speculation
on the role of amino acids at specific positions in the hydrolysis of
cephamycins. We identified 11 positions with amino acids identical in
all AmpC -lactamases hydrolyzing cephamycins at which
ACC-1 carries a different amino acid. Five of them (P 118 Q, Y 135 L, I
155 T, P 213 M, and G 214 E) are nonconservative exchanges and may be
associated with structural modifications which impair the hydrolysis of
methoxy-cephalosporins. The functional significance of the five
nonconservative amino acid exchanges by site-directed mutagenesis is
being analyzed.
The ensemble of phenotypic and genetic characteristics indicates that
the enzyme produced by K. pneumoniae KUS represents a new
type within class C -lactamases. Nomenclature of
plasmid-encoded AmpC -lactamases
similar to that of
TEM--lactamases (13)has not been
systematically standardized. They were designated mainly by their
preferred substrates (the MOX, FOX, and CMY enzymes) or by the place
where strains producing them were first isolated (MIR-1 or BIL-1). For
the new enzyme, neither a preferred substrate nor an outbreak of
infections caused by K. pneumoniae KUS was observed. We
propose the designation Ambler class C, number 1 (ACC-1).
At this time, the number of plasmid-mediated AmpC
-lactamases that has been described is 17. For their
classification, phenotypic characteristics such as preferred substrates
and inhibitory compounds are of less discriminatory power than for
class A enzymes (e.g., low MIC of ceftazidime of CMY-1, or of cefoxitin
of ACC-1). However, the amino acid sequence data are available for all
of them. This allows a genetic subclassification as proposed in Fig. 5.
This tentative subclassification follows the degree of amino acid
sequence identity with CMY-2 (3). Maximum
discrimination of -lactamases could be based on amino
acid fingerprints. Positions in the enzyme occupied by amino acids not
found in any other AmpC -lactamase may be used to define
the molecular individuality of the respective enzyme. The positions
occupied with a unique amino acid describe the sequence individuality
for an enzyme. CMY-2 and ACC-1 are located at the extreme ends on this
scale. ACC-1 carries amino acids not found in any other AmpC
-lactamase at 83 positions. So, this
-lactamase is most distant from the comparable enzymes.
The future evolution of plasmid-encoded AmpC -lactamases
might proceed at a rate comparable to that of the last decade where on
average 1.5 new enzymes were identified per year (3). The novel -lactamases were either closely related to already
described enzymes (CMY-2 or CMY-1 groups) or solitary types (DHA-1,
ACC-1). The selection of strains producing AmpC
-lactamases may be more effective in comparison with
ESBL due to their additional resistance to cephamycins (except ACC-1).
So, monitoring for AmpC -lactamases by including a
cephamycin in the panel of antibiotics used for susceptibility testing
is of major clinical relevance. There is a risk of accumulation of
additional resistance mechanisms in one strain, e.g., impaired
expression of outer membrane proteins or enhanced efflux, which may add
up to pleiotropic resistance including non--lactams (11).
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ACKNOWLEDGMENT |
We thank Anne-Marie Queenan for performing the kinetic analysis
of the ACC-1 -lactamase.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Max von
Pettenkofer-Institut, Pettenkoferstr. 9a, 80336 Munich, Germany. Phone:
0049-89-5160 5268. Fax: 0049-89-5160 5266. E-mail:
Adolf.Bauernfeind{at}mvp-bak.med.uni-muenchen.de.
| |
REFERENCES |
| 1.
|
Barnaud, G.,
G. Arlet,
C. Danglot, and A. Philippon.
1997.
Cloning and sequencing of the gene encoding the AmpC -lactamase of Morganella morganii.
FEMS Microbiol. Lett.
148:15-20[Medline].
|
| 2.
|
Barnaud, G.,
G. Arlet,
C. Verdet,
O. Gaillot,
P. H. Lagrange, and A. Philippon.
1998.
Salmonella enteritidis: AmpC plasmid-mediated inducible -lactamase (DHA-1) with an ampR gene from Morganella morganii.
Antimicrob. Agents Chemother.
42:2352-2358[Abstract/Free Full Text].
|
| 3.
|
Bauernfeind, A.,
Y. Chong, and K. Lee.
1998.
Plasmid-encoded AmpC -lactamases: how far have we gone 10 years after their discovery?
Yonsei Med. J.
39:520-525[Medline].
|
| 4.
|
Bauernfeind, A.,
Y. Chong, and S. Schweighart.
1989.
Extended broad spectrum -lactamase in Klebsiella pneumoniae including resistance to cephamycins.
Infection
17:316-321[Medline].
|
| 5.
|
Bauernfeind, A.,
H. Grimm, and S. Schweighart.
1990.
A new plasmidic cefotaximase in a clinical isolate of Escherichia coli.
Infection
18:294-298[Medline].
|
| 6.
|
Bauernfeind, A.,
I. Stemplinger, and R. Jungwirth.
1996.
Characterization of the plasmidic -lactamase CMY-2, which is responsible for cephamycin resistance.
Antimicrob. Agents Chemother.
40:221-224[Abstract].
|
| 7.
|
Bauernfeind, A.,
I. Stemplinger,
R. Jungwirth,
R. Wilhelm, and Y. Chong.
1996.
Comparative characterization of the cephamycinase blaCMY-1 gene and its relationship with other -lactamase genes.
Antimicrob. Agents Chemother.
40:1926-1930[Abstract].
|
| 8.
|
Bauernfeind, A.,
S. Wagner,
R. Jungwirth,
I. Schneider, and D. Meyer.
1997.
A novel class C -lactamase (FOX-2) in Escherichia coli conferring resistance to cephamycins.
Antimicrob. Agents Chemother.
41:2041-2046[Abstract].
|
| 9.
|
Birnboim, H. C., and J. Doly.
1979.
A rapid alkaline extraction procedure for screening recombinant plasmid DNA.
Nucleic Acids Res.
7:1513-1523[Abstract/Free Full Text].
|
| 10.
|
Boyer-Mariotte, S.,
L. Raskine,
B. Hanau,
A. Philippon,
M. J. Sanson-Le Pors, and G. Arlet.
1998.
Novel plasmid-mediated AmpC-type -lactamase (MOX-2) in a clinical isolate of Klebsiella pneumoniae, abstr. C7, p. 70.
In
Abstracts of the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington, D.C.
|
| 11.
|
Bradford, P. A.,
C. Urban,
N. Mariano,
S. J. Projan,
J. J. Rahal, and K. Bush.
1997.
Imipenem resistance in Klebsiella pneumoniae is associated with the combination of ACT-1, a plasmid-mediated AmpC -lactamase, and the loss of an outer membrane protein.
Antimicrob. Agents Chemother.
41:563-569[Abstract].
|
| 12.
|
Bush, K.,
G. A. Jacoby, and A. A. Medeiros.
1995.
A functional classification scheme for -lactamases and its correlation with molecular structure.
Antimicrob. Agents Chemother.
39:1211-1233[Medline].
|
| 13.
|
Bush, K., and G. Jacoby.
1997.
Nomenclature of TEM -lactamases.
J. Antimicrob. Chemother.
39:1-3[Free Full Text].
|
| 14.
|
Coleman, K.,
D. R. J. Griffin,
J. W. J. Page, and P. A. Upshon.
1989.
In vitro evaluation of BRL 42715, a novel -lactamase inhibitor.
Antimicrob. Agents Chemother.
33:1580-1587[Abstract/Free Full Text].
|
| 15.
|
Datta, N., and P. Kontomichalou.
1965.
Penicillinase synthesis controlled by infectious R factors in Enterobacteriaceae.
Nature (London)
208:239-241[Medline].
|
| 16.
|
Fosberry, A. P.,
D. J. Payne,
E. J. Lawlor, and J. E. Hodgson.
1994.
Cloning and sequencing analysis of blaBIL-1, a plasmid-mediated class C -lactamase gene in Escherichia coli BS.
Antimicrob. Agents Chemother.
38:1182-1185[Abstract/Free Full Text].
|
| 17.
|
Galleni, M.,
F. Lindberg,
S. Normark,
S. Cole,
N. Honoré,
B. Joris, and J.-M. Frère.
1988.
Sequence analysis of three Enterobacter cloacae ampC -lactamase genes and their products.
J. Biochem.
250:753-760.
|
| 18.
|
Gazouli, M.,
L. S. Tzouvelekis,
E. Prinarakis,
V. Miriagou, and E. Tzelepi.
1996.
Transferable cefoxitin resistance in enterobacteria from Greek hospitals and characterization of a plasmid-mediated group 1 -lactamase (LAT-2).
Antimicrob. Agents Chemother.
40:1736-1740[Abstract].
|
| 19.
|
Gonzalez Leiza, M.,
J. C. Perez-Diaz,
J. Ayala,
J. M. Casellas,
J. Martinez-Beltran,
K. Bush, and F. Baquero.
1994.
Gene sequence and biochemical characterization of FOX-1 from Klebsiella pneumoniae, a new AmpC-type plasmid-mediated -lactamase with two molecular variants.
Antimicrob. Agents Chemother.
38:2150-2157[Abstract/Free Full Text].
|
| 20.
|
Higgins, D. G.,
A. J. Bleasby, and R. Fuchs.
1992.
CLUSTAL V: improved software for multiple sequence alignment.
Comput. Appl. Biosci.
8:189-191[Abstract/Free Full Text].
|
| 21.
|
Higgins, D. G., and P. M. Sharp.
1989.
Fast and sensitive multiple sequence alignments on a microcomputer.
CABIOS
5:151-153[Abstract/Free Full Text].
|
| 22.
|
Horii, T.,
Y. Arakawa,
M. Ohta,
T. Sugiyama,
R. Wacharotayankum,
H. Ito, and N. Kato.
1994.
Characterization of a plasmid-borne and constitutively expressed blaMOX-1 gene encoding ampC-type -lactamase.
Gene
139:93-98[Medline].
|
| 23.
|
Jacoby, G. A., and J. Tran.
1999.
Sequence of the MIR-1 -lactamase gene.
Antimicrob. Agents Chemother.
43:1759-1760[Abstract/Free Full Text].
|
| 24.
|
Jaurin, B., and T. Grundström.
1981.
AmpC cephalosporinase of Escherichia coli K12 has a different evolutionary origin from that of -lactamases of the penicillin type.
Proc. Natl. Acad. Sci. USA
78:4897-4901[Abstract/Free Full Text].
|
| 25.
|
Lindberg, F., and S. Normark.
1986.
Sequence of the Citrobacter freundii OS60 chromosomal ampC -lactamase gene.
Eur. J. Biochem.
156:441-445[Medline].
|
| 26.
|
Lodge, J. M.,
S. D. Minchin,
L. J. V. Piddock, and S. J. W. Busby.
1990.
Cloning, sequencing and analysis of the structural gene and regulatory region of the Pseudomonas aeruginosa chromosomal ampC -lactamase.
Biochem. J.
272:627-631[Medline].
|
| 27.
|
Marchese, A.,
G. Arlet,
G. C. Schito,
P. H. Lagrange, and A. Philippon.
1998.
Characterization of FOX-3, an AmpC-type plasmid-mediated -lactamase from an Italian isolate of Klebsiella oxytoca.
Antimicrob. Agents Chemother.
42:464-467[Abstract/Free Full Text].
|
| 28.
|
Matthew, M.,
A. M. Harris,
M. J. Marshall, and G. W. Ross.
1975.
The use of analytical isoelectric focussing for detection and identification of -lactamases.
J. Gen. Microbiol.
88:169-178[Medline].
|
| 29.
|
National Committee for Clinical Laboratory Standards.
1997.
Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 4th ed., vol. 17, no. 2. Approved standard M7-A4.
National Committee for Clinical Laboratory Standards, Wayne, Pa.
|
| 30.
|
Nayler, J. H. C.
1987.
Resistance to -lactams in Gram-negative bacteria: relative contributions of -lactamase and permeability limitations.
J. Antimicrob. Chemother.
19:713-732[Free Full Text].
|
| 31.
|
Nomura, K., and T. Yoshida.
1990.
Nucleotide sequence of the Serratia marcescens SR50 chromosomal ampC -lactamase gene.
FEMS Microbiol. Lett.
70:295-300.
|
| 32.
|
Papanicolaou, G. A.,
A. A. Medeiros, and G. A. Jacoby.
1990.
Novel plasmid-mediated -lactamase (MIR-1) conferring resistance to oxyimino- and -methoxy -lactams in clinical isolates of Klebsiella pneumoniae.
Antimicrob. Agents Chemother.
34:2200-2209[Abstract/Free Full Text].
|
| 33.
|
Richter, H. G.,
P. Angehrn,
C. Hubschwerlen,
M. Kania,
M. G. Page,
J. L. Specklin, and F. K. Winkler.
1996.
Design, synthesis, and evaluation of 2 beta-alkenyl penam sulfone acids as inhibitors of -lactamases.
J. Med. Chem.
39:3712-3722[Medline].
|
| 34.
|
Saitou, N., and M. Nei.
1987.
The neighbor-joining method: a new method for reconstructing phylogenetic trees.
Mol. Biol. Evol.
4:406-425[Abstract].
|
| 35.
|
Sambrook, J.,
E. F. Fritsch, and T. Maniatis.
1989.
Molecular cloning: a laboratory manual, 2nd ed.
Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.
|
| 36.
|
Sanger, F.,
S. Nicklen, and A. R. Coulson.
1977.
DNA sequencing with chain-terminating inhibitors.
Proc. Natl. Acad. Sci. USA
74:5463-5467[Abstract/Free Full Text].
|
| 37.
|
Tzouvelekis, L. S.,
E. Tzelepi,
A. F. Mentis, and A. Tsakaris.
1993.
Identification of a novel plasmid-mediated -lactamase with chromosomal cephalosporinase characteristics from Klebsiella pneumoniae.
J. Antimicrob. Chemother.
31:645-654[Abstract/Free Full Text].
|
| 38.
|
Verdet, C.,
G. Arlet,
S. Ben Redjeb,
A. Ben Hassen,
P. H. Lagrange, and A. Philippon.
1998.
Characterization of CMY-4, an AmpC-type plasmid-mediated -lactamase in a Tunisian clinical isolate of Proteus mirabilis.
FEMS Microbiol. Lett.
169:235-240[Medline].
|
Antimicrobial Agents and Chemotherapy, August 1999, p. 1924-1931, Vol. 43, No. 8
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
