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Antimicrobial Agents and Chemotherapy, February 1999, p. 307-313, Vol. 43, No. 2
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Characterization of SFO-1, a Plasmid-Mediated
Inducible Class A 
-Lactamase from Enterobacter
cloacae
Yoshimi
Matsumoto1,2,* and
Matsuhisa
Inoue1
Department of Microbiology, Kitasato
University School of Medicine, Sagamihara,1 and
Medicinal Biology Research Laboratories, Fujisawa
Pharmaceutical Co., Ltd., Osaka,2 Japan
Received 1 April 1998/Returned for modification 23 July
1998/Accepted 24 November 1998
 |
ABSTRACT |
Enterobacter cloacae 8009 produced an inducible class A
-lactamase which hydrolyzed cefotaxime efficiently. It also
hydrolyzed other -lactams except cephamycins and carbapenems. The
activity was inhibited by clavulanic acid and imipenem. The
bla gene was transferable to Escherichia coli
by electroporation of plasmid DNA. The molecular mass of the
-lactamase was 29 kDa and its pI was 7.3. All of these phenotypic
characteristics of the enzyme except for inducible production resemble
those of some extended-spectrum class A -lactamases like FEC-1. The
gene encoding this -lactamase was cloned and sequenced. The deduced
amino acid sequence of the -lactamase was homologous to the AmpA
sequences of the Serratia fonticola chromosomal enzyme
(96%), MEN-1 (78%), Klebsiella oxytoca chromosomal
enzymes (77%), TOHO-1 (75%), and FEC-1 (72%). The conserved
sequences of class A -lactamases, including the S-X(T)-X(S)-K motif,
in the active site were all conserved in this enzyme. On the basis of
the high degree of homology to the -lactamase of S. fonticola, the enzyme was named SFO-1. The ampR gene
was located upstream of the ampA gene, and the AmpR
sequence of SFO-1 had homology with the AmpR sequences of the
chromosomal -lactamases from Citrobacter diversus
(80%), Proteus vulgaris (68%), and Pseudomonas aeruginosa (60%). SFO-1 was also inducible in E. coli. However, a transformant harboring plasmid without intact
ampR produced a small amount of -lactamase
constitutively, suggesting that AmpR works as an activator of
ampA of SFO-1. This is the first report from Japan
describing an inducible plasmid-mediated class A -lactamase in
gram-negative bacteria.
| |
INTRODUCTION |
Since the introduction of
extended-spectrum cephalosporins into clinical use, gram-negative
bacteria have reacted to them mainly by producing various new types of
plasmid-mediated extended-spectrum -lactamases, in addition to
overproducing chromosomal -lactamases. Bush's classification of
-lactamases was updated in 1995 (5). A total of 178 kinds
of different -lactamases were included in that classification.
Recently, additional extended-spectrum -lactamases which hydrolyze
oxyimino-cephalosporins have been isolated all over the world (5,
7, 12, 13, 14, 21, 27, 28). Most of them are related to the TEM
and SHV families of -lactamases. However, in Japan,
extended-spectrum -lactamases derived from these families have never
been isolated. On the other hand, different types of extended-spectrum
-lactamases classified as 2be and 2e (class A) (10, 17, 20,
31), 1 (class C) (8), and 4 (class B) (11,
30) have been isolated. The differences in enzyme populations are
thought to arise from the various clinical uses of antibacterial
agents. We reported on plasmid-mediated oxyimino-cephalosporin-hydrolyzing class A -lactamase FEC-1 in 1988 (20). Although it was not from a clinical isolate, the possibility of the appearance of such an enzyme was suggested. Since
then, a similar type of enzyme has been identified in Japan (31).
Enterobacter cloacae is known to produce inducible
chromosomal -lactamases. Overproduction or constitutive production
of this enzyme causes resistance to most -lactams except carbapenems (16, 29) without the loss of any porin. On the other hand, an amino acid insertion into the omega loop region of the class C
-lactamase causes substrate specificity extension to
extended-spectrum -lactams (24). We found 1 ceftizoxime-susceptible strain among 12 cefotaxime-resistant E. cloacae strains isolated at Teikyo University in 1988. The strain
produced an inducible enzyme which hydrolyzed cefotaxime efficiently.
The phenotypic characteristics of this enzyme resembled those of FEC-1
except for the inducible production. Since induction of
plasmid-mediated -lactamase is known to be rare in gram-negative
bacteria, the origin of this enzyme is of great interest. In this study
the gene was cloned and was further analyzed.
| |
MATERIALS AND METHODS |
Bacterial strains.
E. cloacae 8009 was isolated
clinically in 1988 and was kindly provided by K. Ubukata of Teikyo
University (Tokyo, Japan). Competent Escherichia coli DH10B
was obtained commercially from GIBCO-BRL. The constructed strains and
plasmids are described in Table 1.
Plasmids.
pHSG396 was from Takara Shuzo (Otsu, Japan).
Antibiotics.
The antibiotics used in this study were
commercially available. Imipenem-cilastatin (Banyu, Tokyo, Japan),
ceftazidime (Glaxo Japan, Tokyo, Japan), cefoperazone (Toyama, Tokyo,
Japan), moxalactam (Shionogi, Osaka, Japan), aztreonam (Eisai, Tokyo,
Japan), cefpiramide (Sumitomo, Osaka, Japan), ceftizoxime (Fujisawa,
Osaka, Japan), cefotaxime (Chugai, Tokyo, Japan), cefmenoxime (Takeda,
Osaka, Japan), ceftriaxone (Roche, Tokyo, Japan), cefuroxime (Glaxo), cefotiam (Takeda), cefoxitin (Banyu), cefamandole (Shionogi), cefazolin
(Fujisawa), cephalothin (Shionogi), cephaloridine (Shionogi), and
ampicillin (Fujisawa) were used. Cefoselis (FK037) (22), clavulanic acid, and nitrocefin were synthesized in our laboratories.
Susceptibility testing.
MICs were determined with serial
dilutions of antibiotics in Mueller-Hinton medium with inoculum sizes
of 104 and 106 CFU per spot. The MICs were read
as the lowest concentration of antibiotic that inhibited visible growth
after 18 h of incubation at 37°C.
Preparation of -lactamase.
Exponentially growing cells of
the test strains in Trypticase soy broth (BBL, Becton Dickinson
Microbiology Systems, Cockeysville, Md.) were harvested, washed once,
and resuspended in a 1/20 volume of 50 mM potassium phosphate buffer
(pH 7.0). The suspension was sonically disrupted and the debris was
removed by centrifugation (15,000 × g, 30 min).
-Lactamase was partially purified by ion-exchange chromatography
with POROS 20HS and a BioCAD work station (PerSeptive Biosystems,
Tokyo, Japan).
Assay of -lactamase activity.
-Lactamase activity was
determined spectrophotometrically (UV-2200; Shimadzu) at 37°C in
0.067 M potassium phosphate buffer (pH 7.0).
-Lactamase inhibitor susceptibility.
Susceptibility to
-lactamase inhibitors was determined as mentioned previously
(20).
Analytical isoelectric focusing.
Isoelectric focusing was
performed with crude extracts with an LKB Ampholine PAG plate (pH 3.5 to 9.5) and an analytical electrofocusing system (LKB Stockholm,
Bromma, Sweden). -Lactamase activity was detected by overlaying the
gel with filter paper containing nitrocefin (0.5 mg/ml).
Inducibility of -lactamase.
Imipenem (0.1 µg/ml) was
added to a mid-logarithmic-phase culture, and the culture was incubated
for 2 more h. The cells were harvested by centrifugation
(10,000 × g, 10 min), resuspended in a 1/10 volume of
0.067 M potassium phosphate buffer (pH 7.0), and disrupted by
sonication. The -lactamase activity and protein concentration were
measured, and specific activities were compared.
Transformation study.
Plasmid DNA was isolated from E. cloacae 8009 and was used to transform E. coli DH10B by
electroporation. Ampicillin-resistant colonies with different plasmids
were selected and named TF-L (E. coli DH10B/pFCX300L) and
TF-M (E. coli DH10B/pFCX300M). E. cloacae 199S (a
chromosomal -lactamase-deficient strain) was also used as a recipient.
Cloning of -lactamase gene.
Plasmid DNA from E. cloacae 8009 was partially digested with Sau3AI and was
ligated into the BamHI site of pHSG396 (see Fig. 1). The
ligation mixture was used to transform E. coli DH10B. Transformants harboring plasmids which have short fragment insertions were selected (TF2-2, E. coli DH10B/pFCX310; and TF2-3,
E. coli DH10B/pFCX320).
Alternatively, the DNAs of two plasmids, pFCX300L and pFCX300M, were
each digested with EcoRI and were cloned into pHSG396 to get
TF-L7 (E. coli DH10B/pFCX301) and TF-M4 (E. coli
DH10B/pFCX302).
DNA sequence analysis.
DNA sequence analysis was performed
by the PCR cycle sequencing method with the Sequthermo kit (Epicenter
Technology) and the thermosequenase kit (Amersham) and with the LI-COR
4000LS system. For determination of the sequence of ampA,
pFCX310 and pFCX320 were used as templates. The AmpR gene and franking
region were sequenced by using pFCX301 and pFCX302 and their deletion plasmids as templates and primers synthesized from the sequences of
pFCX310 and pFCX320. The ABI PRISM 310 Genetic Analyzer (Applied Biosystems) was also used. Homology was analyzed by the FASTA program
of the DNA Data Base of Japan (DDBJ).
Nucleotide sequence accession number.
The nucleotide
sequence data reported in this paper will appear in the DDBJ, EMBL, and
GenBank nucleotide sequence databases under accession no. AB003148.
| |
RESULTS |
Characteristics of -lactamase from E. cloacae 8009.
E. cloacae 8009 was resistant to various -lactam
antibiotics including extended-spectrum cephalosporins such as
cefotaxime, cefoperazone, cefoselis, and monobactam (aztreonam) but
excluding carbapenems (Table 2). However,
strain 8009 was not as resistant to such oxyimino-cephalosporins
(ceftizoxime and ceftazidime) as the high-level producers of
chromosomal -lactamase (Table 2). Also, E. cloacae 8009 was not resistant to the other antibiotics tested (Table
3). The -lactamase was partially
purified from E. cloacae 8009 by ion-exchange
chromatography. The molecular mass of this enzyme was 29 kDa by sodium
dodecyl sulfate-polyacrylamide gel electrophoresis, and its pI was 7.3. Values of kinetic parameters were determined (Table
4). The enzyme hydrolyzed
oxyimino-cephalosporins, in addition to cephaloridine and ampicillin.
Ceftazidime was the most stable among the cephalosporins tested. The
hydrolysis of cephamycin (cefoxitin), oxacephem (moxalactam), and
carbapenem (imipenem) by this enzyme was not detectable (data not
shown). The enzyme activity was inhibited by clavulanic acid and
imipenem (Table 5) but was not inhibited
by EDTA and P-chloromercuribenzoate (data not shown). These
characteristics resembled those of FEC-1 (20) and some other
class A enzymes (5) reported previously.
Effect of inducer on the -lactamase production in E. cloacae 8009.
Imipenem induced cefotaxime-hydrolyzing
-lactamase production in E. cloacae 8009, and the
specific cefotaxime-hydrolyzing activity was about 10 times higher when
it was induced (Table 6).
Transformation of E. coli.
E. cloacae 8009 had
plasmids of three different sizes (Fig.
1). E. coli DH10B was
transformed by electroporation with total plasmid DNA isolated from
E. cloacae 8009 and was selected on plates containing
cefotaxime at 1 µg/ml. The largest plasmid, pFCX300L, was detected in
every transformant (TF-L) except one (TF-M), in which middle-size
plasmid pFCX300M was detected (Fig. 1). Transconjugation from E. cloacae 8009 to E. coli was unsuccessful, suggesting
that the gene is on a nonconjugable R plasmid.
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FIG. 1.
Agarose gel electrophoresis of plasmid DNAs from
E. cloacae 8009. Lane A, HindIII-digested
bacteriophage  DNA; lane B, E. cloacae 8009. L, large
plasmid; M, medium-size plasmid; S, small plasmid.
|
|
The antibiotic susceptibility patterns of these transformants were
similar to those of FEC-1-producing
E. coli DH5
except
for cefoselis susceptibility, although TF-M was more susceptible
than
E. coli DH5
/FEC-1 (Table
2). The MICs differed for TF-M
and TF-L, perhaps due to a difference in copy
numbers.
Cloning and characterization of the -lactamase gene.
The
plasmid-mediated -lactamase gene of E. cloacae 8009 was
cloned into vector plasmid pHSG396 and was used to transform E. coli DH10B (Fig. 2). Two
transformants that have plasmids (pFCX310 and pFCX320) recombined with
a partially digested Sau3AI fragment and that had an
insertion of nearly 2.2 kb were selected. The sequence obtained was
analyzed by a search of the GenBank database (GENETYX-MAC/CD) for a
homologous sequence, and the search revealed the existence of a
-lactamase gene similar to that for a Klebsiella oxytoca
chromosomal enzyme (2). The initiation codon and stop codon
were designated on the basis of the homologies of their sequences with
those for the initiation codon and stop codon of the K. oxytoca -lactamase gene. Following a search for a homologous amino acid sequence, the highest degree of homology was seen with the
-lactamase from Serratia fonticola. We named the enzyme
SFO-1. The alignments of the deduced amino acid sequence of SFO-1 with those of homologous enzymes are shown in Fig.
3. Sequence identities were 96, 78, 77, and 75% with S. fonticola -lactamase (P80545), MEN-1
(3), K. oxytoca chromosomal enzymes
(2), and TOHO-1 (11), respectively. The homology
between SFO-1 and FEC-1 was 72%. The conserved sequences of class A
-lactamases including the 70S-X(T)-X(S)-K motif in the active site
were all conserved in this enzyme (1). It is noteworthy that
there was an ampR-related sequence that inversely followed
the upstream region of ampA. However, the
ampR-like sequence was not intact in pFCX310 or pFCX320. The
sequence of SFO-1 also had 70% homology with the sequences of the
inducible chromosomal -lactamases of Citrobacter diversus (25) and Proteus vulgaris (24).
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FIG. 3.
Alignment of deduced amino acid sequence of SFO-1 (AmpA)
with the sequences of homologous enzymes. The amino acid numbering for
the class A -lactamase is used (1). The S-X(T)-X(S)-K
motif with the active-site serine is shaded. Asterisks indicate the
conserved amino acid residues among these class A sequences.
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|
Characterization of ampR of SFO-1.
To obtain the
full length of ampR with ampA on the same
fragment, EcoRI-restricted fragments from pFCX300L and
pFCX300M were cloned into pHSG396 (Fig. 2). Two kinds of plasmids,
pFCX301 from pFCX300M and pFCX302 from pFCX300L, were obtained. They
seemed to have the same fragment in different directions from the
results of restriction mapping and sequencing of both ends. By using
these transformants as a template, the sequence of the flanking region of ampA was read as described in Materials and Methods. From
the homology with the ampR gene of P. vulgaris
(6), a complete ampR gene was identified upstream
from ampA. The deduced amino acid sequence of AmpR had 80, 68, 60, and 56% similarities with the AmpR sequences of the
chromosomal -lactamases from C. diversus (15),
P. vulgaris (6), Pseudomonas
aeruginosa (19), and S. marcescens
(23), respectively. The alignments of these AmpR sequences
are shown in Fig. 4.
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FIG. 4.
Alignment of deduced amino acid sequence of AmpR of
SFO-1 with homologous AmpR sequences. Asterisks indicate the conserved
amino acid residues.
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|
Role of ampR gene.
The inducibility of
-lactamase production in each E. coli transformant was
determined as described in Materials and Methods (Table 6, experiment
2). In E. coli strains harboring pFCX310 and pFCX320 with an
incomplete ampR gene, -lactamase was not induced by
imipenem, and the amount of -lactamase produced in them stayed low.
On the other hand, in E. coli strains harboring pFCX301 and
pFCX302 with a complete ampR gene on the same vector, -lactamase production was induced by the addition of imipenem. E. coli DH10B harboring native pFCX300L and pFCX300M also
produced -lactamase inducibly, although specific activities were
lower than those for E. cloacae 8009.
Susceptibilities of transformants to various antibiotics.
The
patterns of susceptibility to various agents for the transformants that
were obtained are presented in Tables 2 and 3. The MICs were higher for
E. cloacae 8009 than those for any of the other
transformants tested. Moreover, E. cloacae 8009 was also
resistant to cefoxitin and moxalactam, suggesting that the strain
produces a fair amount of chromosomal cephalosporinase, although it was
not detectable by analytical isoelectric focusing. The MICs for
transformants harboring pHSG396-derived plasmids were higher than the
MICs for transformants harboring low-copy-number original plasmids. The
effect of copy number was larger than the effect of the AmpR activator
on the SFO-1 producer.
| |
DISCUSSION |
The SFO-1 -lactamase isolated from E. cloacae 8009 seems to be
more threatening than the common TEM-1- or TEM-2-type -lactamase because it has a broad spectrum of activity and hydrolyzes various -lactam antibiotics but not cephamycin, oxacephem, or carbapenem. However, E. cloacae is known to gain resistance to
-lactams easily as a result of mutations of the regulatory genes for
chromosomal inducible -lactamase, making it a high-level
-lactamase producer (4, 6, 16, 18). In fact, the level of
resistance of E. cloacae 8009 to ceftizoxime, ceftazidime,
and moxalactam was lower than those for strains that constitutively
produce large amounts of chromosomal -lactamase (Table 2). If
E. cloacae 8009 was a high-level producer of chromosomal
-lactamase, it would be almost impossible to predict the presence of
a -lactamase like SFO-1 on the basis of patterns of susceptibility
to various -lactams. Moreover, the strain would have no need to
acquire SFO-1 genes for defense. E. cloacae 8009 was also
resistant to cefoxitin, in contrast to the SFO-1-producing transformant
derived from -lactamase-negative E. cloacae 199S. The
cefoxitin resistance of E. cloacae 8009 is considered to
come from a porin change or small amounts of chromosomal -lactamase
produced by the strain, although it was difficult to detect chromosomal
-lactamase by isoelectric focusing. SFO-1 seems to have an important
role in the -lactam resistance of E. cloacae 8009. SFO-1
could be an effective weapon that various gram-negative bacteria could
use to resist -lactams.
-Lactamase is usually produced constitutively in E. coli,
which has no ampR gene (4). SFO-1 was produced
constitutively in TF2-2 and TF2-3, as shown in Table 6.
Are there any merits to the coexistence of ampR with
ampA? In gram-negative bacteria, virtually all of the known
plasmid-mediated -lactamases are produced constitutively, although
SFO-1 was produced inducibly. The presence of ampR seems to
be a disadvantage for the host strain, because E. cloacae
becomes highly resistant to -lactams when -lactamase production
is changed from inducible to constitutive. However, the amount of
-lactamase was larger in the strain which has both ampR
and ampA on the plasmid, which indicates that AmpR acts as
an activator as well as a repressor (4). The coexistence of
ampR with ampA is considered to aid in the
progression of resistance. In fact, after induction TF-L7 and TF-M4,
which had ampR, produced SFO-1 in amounts more than 10 times
larger than the amounts produced by TF2-2 and TF2-3, which did not have
ampR, although they have SFO-1 on the same vector (Table 6).
However, the MICs of the cephalosporins for the transformants were not
dramatically influenced by the presence of ampR. The low
level of resistance of TF-L was considered to come from the low copy
number of plasmid pFCX300L.
Concerning the origin of the plasmid-mediated -lactamase, it is most
possible that the ampA of SFO-1 is from S. fonticola (8), because the AmpA sequences of both
E. cloacae 8009 and S. fonticola had a high
degree of homology (95.5%), although there is no information about the
AmpR of S. fonticola. The AmpA sequence of E. cloacae 8009 also had a high degree of homology with those of the
enzyme from K. oxytoca and MEN-1, although the latter two enzymes are constitutively produced. C. diversus is another
possible source because its AmpA and AmpR sequences were 70 and 80%
homologous to those of E. cloacae 8009, respectively. In the
PCR study with primers designed to detect ampA and
ampR of SFO-1, no strains of ordinary gram-negative
organisms produced both amplified fragments, although we have not
examined S. fonticola (data not shown). S. fonticola, a kind of flora usually isolated from well waters and springs, is not well known because it is not a pathogenic organism (8). However, because it is a possible source of a
plasmid-mediated resistance factor, it is necessary to pay attention to
minor species as possible resistance gene donors, even if they are uncommon.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Medicinal
Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 1-6, 2-Chome, Kashima, Yodogawa-ku, Osaka, 532 Japan. Phone: (06) 390-1146. Fax: (06) 304-1192. E-mail:
yoshimi_matsumoto{at}po.fujisawa.co.jp.
| |
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Antimicrobial Agents and Chemotherapy, February 1999, p. 307-313, Vol. 43, No. 2
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
