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Antimicrobial Agents and Chemotherapy, April 2000, p. 1070-1074, Vol. 44, No. 4
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Nucleotide Sequence of the
blaRTG-2 (CARB-5) Gene and Phylogeny of a New
Group of Carbenicillinases
Daniele
Choury,1,*
Marie-France
Szajnert,2
Marie-Laure
Joly-Guillou,3
Kemal
Azibi,2
Marc
Delpech,1 and
Gérard
Paul4
Laboratoire de Biologie Moléculaire des
Cellules Eucaryotes,1 INSERM
U129,2 and Laboratoire de Recherche
en Microbiologie,4 UFR Cochin Port-Royal, 75014 Paris, and UFR Xavier-Bichat, 75018 Paris,3 France
Received 27 July 1999/Returned for modification 16 November
1999/Accepted 30 December 1999
 |
ABSTRACT |
We determined the nucleotide sequence of the bla gene
for the Acinetobacter calcoaceticus 
-lactamase
previously described as CARB-5. Alignment of the deduced amino acid
sequence with those of known -lactamases revealed that CARB-5
possesses an RTG triad in box VII, as described for the Proteus
mirabilis GN79 enzyme, instead of the RSG consensus
characteristic of the other carbenicillinases. Phylogenetic studies
showed that these RTG enzymes constitute a new, separate group,
possibly ancestors of the carbenicillinase family.
| |
TEXT |
The assumption that
carbenicillin-inactivating -lactamases were a homogeneous
cluster of enzymes confined to Pseudomonas aeruginosa
strains (9) did not last long. First, some
Pseudomonas-specific enzymes may have spread, on rare
occasions, to various enterobacteria (19). Second, evidence
is accumulating that, in addition to Proteus mirabilis in
Japan (27) and other enterobacteria, strains of Vibrio
cholerae, Alcaligenes xylosoxidans, Aeromonas
hydrophila, and Acinetobacter calcoaceticus also
produce such -lactamases (SAR-1 and CARB-6 for V. cholerae and PSE-1, AER-1, and CARB-5 for A. xylosoxidans, A. hydrophila, and
A. calcoaceticus, respectively). Major progress in the
comprehension and classification of carbenicillinases is expected from
structural data. Four main structures account for the diversity of
carbenicillinases. The major structure is that of the CARB group, which
includes CARB-1 (PSE-4), CARB-2 (PSE-1), CARB-3 (17,
18), CARB-4 (22, 25), CARB-6
(6), and P. mirabilis N29 -lactamase
(12). The three other enzyme structures do not belong, at
this time, to any particular group: PSE-3 -lactamase (5),
P. mirabilis GN79 (24), and AER-1 -lactamases (25). Sequence information is currently
unavailable for two -lactamases, CARB-5 and SAR-1, which have
been defined as carbenicillinases due to their hydrolytic properties.
Our aim was to determine the nucleotide sequence of the bla
gene (CARB-5) from A. calcoaceticus strain A85-145, the
resistance properties and enzyme characteristics of which have been
previously published (21).
Clinical strains producing CARB-5.
Several clinical isolates
of Acinetobacter calcoaceticus subsp. anitratus,
resistant to ticarcillin alone but susceptible to ticarcillin in
combination with clavulanic acid, have been found to produce a new
-lactamase, with a pI of 6.35 (14). Its molecular weight
of 28,000 and substrate profile are typical of a
carbenicillin-hydrolyzing enzyme. The enzyme was inhibited by
anti-CARB-3 serum, p-chloromercuribenzoate, cloxacillin,
clavulanic acid, and sulbactam (21).
Nucleotide sequence of blaCARB-5.
Several sets of oligonucleotide primer pairs specific for most CARB
sequences were unsuccessfully used for amplification. Unexpected
positive results were obtained with primers based on the sequence of
the P. mirabilis GN79 bla gene (24).
The nucleotide sequence of the structural gene was then
determined by direct sequencing of PCR fragments
amplified from chromosomal DNA extracted by the X-Trax procedure
(6) with two pairs of synthetic primers (Table
1) comprising the whole reference
sequence of the P. mirabilis GN79 gene. Amplification by PCR
was performed at 44°C as described elsewhere (6).
The nucleotide sequence of the PCR product (912 bp) contains a 905-bp
open reading frame. The coding region is 897 bp (positions
12 to 908)
and encodes a protein of 298 amino acids (Fig.
1).
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FIG. 1.
Nucleotide and deduced amino acid sequence of A. calcoaceticus -lactamase (CARB-5). The active site is boxed,
and the differences from the P. mirabilis GN79
-lactamase sequence are underlined.
|
|
CARB-5 is a class A -lactamase.
Analysis of the deduced
amino acid sequence showed that specific motifs were very similar to
those of class A -lactamases: the bla active-site (STFK)
tetrad at positions 72 to 75 (70 to 73 according to the standard
numbering scheme of Ambler [2]) and the consensual
boxes I to VI described by Joris et al. (15) were conserved
(Fig. 2). In contrast, box VII
consisted of an RTG triad instead of the conserved RSG motif specific
to the carbenicillinases (3). All the residues
specific to class A -lactamases were conserved except that the Leu
at position 177 (164 according to Ambler numbering) was replaced with a
Pro, as reported for P. mirabilis GN79 (24).
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FIG. 2.
Multiple sequence alignment of the amino acid sequences
of the CARB-1, CARB-2, CARB-3, CARB-4, CARB-6, P. mirabilis
N29 and GN79, and CARB-5 -lactamases. The shaded boxes (I to VII)
correspond to amino acids conserved in all penicillin-recognizing
enzymes, as identified by Joris et al. (15). Alpha-helix and
beta-barrel motifs are from the PC1 crystal structure (3,
10). Asterisks indicate the conserved residues specific for class
A -lactamases. Amino acid changes are indicated as black letters on
a white background. Sequences are numbered according to the method of
Ambler (2).
|
|
Nucleic and amino acid sequence analyses with the BLAST and FASTA
(
1) programs showed substantial homology (more than 99%)
to
the
P. mirabilis GN79 sequence but only 43, 44, and 45%
identity
to the SHV (
8), CARB (
17,
18), and TEM
(
11)
-lactamases,
respectively. Pairwise alignment
between the CARB-5 and GN79 nucleic
acid sequences revealed four
mutations in the coding region (C
to A at position 24, C to T at 163, G
to T at 450, and C to A
at 520) giving rise to three amino acid
substitutions (Fig.
1 and
2): Gln to Lys at position 5 (2 according to
Ambler), Ala
to Val at position 51 (48 according to Ambler
numbering), and
Pro to Thr at position 170 (167 according to
Ambler numbering).
Multiple sequence alignment (
28) of
the CARB-5 amino acid sequence
with the previously described sequences
of the CARB-1, CARB-2
and CARB-3 (
17,
18), CARB-4 (
22,
25), CARB-6 (
6),
P. mirabilis N29
(
12), and
P. mirabilis GN79 (
24)
-lactamases
showed that the first amino acid change (Gln to Lys) was
located
outside the sequence of the other carbenicillinases, the second
(Ala to Val) was common to all the carbenicillinase sequences,
and the
third (Pro to Thr) was unique among all aligned sequences
(Fig.
2).
Although the CARB-5 enzyme contains the specific Arg 234 residue
characteristic of carbenicillinases, CARB-5 seems to be only
distantly
related to these enzymes. Moreover, it also contains
RTG box VII,
reported for the first and only time for
P. mirabilis GN79
(
24), instead of the RSG usually encountered in
carbenicillinases
(
3).
Phylogenetic analysis.
A phylogenetic tree was constructed
from ClustalW multiple sequence alignment of 29 class A
-lactamases (Table 2), using the neighbor-joining method (23). This tree (Fig.
3) exhibited two major branches. One,
including cephalosporinases, carbapenemases, and Staphylococcus
aureus PC1 enzyme, constitutes the outgroup. The other ramifies
into three main subbranches corresponding to three distinct groups. One
of these contains the SHV and TEM enzymes and the second consists of
the carbenicillinases according to the previously proposed scheme
(4). Surprisingly, CARB-5 clustered with P. mirabilis GN79 to make up a third group distantly related to
the other two groups. These results were confirmed by other methods
(data not shown): PROTPARS (protein sequence parsimony method), PRODIST (protein distances) from the PHYLIP
package of Joseph Felsenstein (Department of Genetics at the University
of Washington), and Web Gene Bee services (Belozersky Institute, Moscow
State University) (13). The reliability of the
phylogenetic trees was estimated by bootstrapping (26). The
node and branching leading to the CARB-5-GN79 cluster were confirmed
in 997 and 1,000 of 1,000 bootstrap tests (data not shown). The
general configuration of this tree differs slightly from that in Fig. 3
(neighbor-joining method), with PC1, BLAC_BACSU, and BLA1_BACMY
making up a separate outgroup.
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FIG. 3.
Dendrograms obtained from multiple alignment of 29 class
A -lactamases according to the neighbor-joining method
(23). Branch length values represent relative phylogenetic
distances.
|
|
CARB-5 (RTG-2) and P. mirabilis GN79 (RTG-1)
-lactamases are members of a new carbenicillinase group called
RTG.
Nucleotide and amino acid sequence features and biochemical
properties of the CARB-5 and P. mirabilis GN79 enzymes
(21, 24) exhibit a great degree of similarity. Although the
homology of these sequences with known CARB structures is low, they can be related to the carbenicillinase group in regard to their biochemical properties. However, despite their sequence identities, the
-lactamase neutralization assay for CARB-5 with anti-CARB serum gave
results in conflict with those obtained for GN79 in the original study. The P. mirabilis GN79 -lactamase was not neutralized by
serum raised against the P. mirabilis N29 -lactamase,
which fully neutralized PSE-1 and PSE-4 (27). In contrast,
CARB-5 was inhibited by anti-CARB-3 serum that also reacts with other
CARB enzymes, including PSE-1 and PSE-4. Moreover, this result
accounted for the designation of CARB-5. Such discrepancy in the
results may be due to different technical approaches: the
neutralization of GN79 was studied in a dilute-liquid-phase assay,
whereas CARB-5 was studied undiluted in a specific gel assay. The
liquid-phase assay is known to be more specific than the gel assay,
which is more sensitive. Indeed, neutralization in gel makes it
possible for the three-dimensional structure of the -lactamase to
combine with low-affinity heterologous antibodies. Such unexpected
cross-neutralization in the gel assay has also been reported for the
TEM and SHV -lactamases with anti-TEM-1 serum (20).
In the CARB-5 amino acid sequence, all residues specific to class A
-lactamases are conserved, as are six of seven boxes
(
15). The most striking feature is the presence of an RTG
triad
(box VII), as for GN79, instead of the RSG characteristic of the
CARB family and unique among class A
-lactamases. The CARB-5
and
GN79 enzymes seem to constitute a new carbenicillinase
group.
RTG-1 and RTG-2 are possible ancestors of the
carbenicillinase family.
Phylogenetic trees (Fig. 3 and
4) clearly show the evolution of 29 -lactamases. S. aureus PC1 and the two
Bacillus cephalosporinases (BLAC_BACSU and
BLA1_BACMY), all issued from gram-positive bacteria, appeared
early in evolution. Analysis of 18 class A -lactamases has shown the
origin of the enzyme to be the actinomycetes, from which it migrated
first into nonactinomycete gram-positive lines, such as
Bacillus, and later into the gram-negative bacteria
(16). This is consistent with the results of Huletsky et al.
(11) and supports their suggestion that the -lactamases
from gram-negative and gram-positive bacteria constitute two distinct
groups. This would imply that the bla genes of gram-positive
and Bacillus species appeared early in evolution, followed
by the PSE and CARB enzymes and later by the SHV and TEM enzymes found
in enteric bacteria. If we consider the evolutionary representation of
the phylogenetic tree (Fig. 4), CARB-5 and GN79 are tightly linked and
appeared earlier in evolution than other CARB enzymes, which make a
separate cluster.
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FIG. 4.
Evolutionary representation of unrooted phylogenetic
tree. The phylogenetic tree was obtained as described in the legend to
Fig. 3.
|
|
Interestingly, CARB-5 and GN79 are chromosomally acquired genes. It has
been suggested that
-lactamases evolved and spread
from the
ancestral source;
Streptomyces chromosomal
penicillin-recognizing
enzymes would be the oldest known enzymes of
this type (
7).
The LEN-1 chromosomal enzyme was
previously thought to be the
ancestor of the SHV family
(
11). A similar hypothesis could
be put forward for the GN79
and CARB-5 group, which would then
be the ancestors of the
carbenicillinase
family.
Thus, the carbenicillinase encoded in the
A. calcoaceticus
chromosome is a novel carbenicillinase, structurally related to
the
P. mirabilis GN79 enzyme. These two chromosomal enzymes may
be considered to be ancestors of the carbenicillinase
family.
All these features lead us to suggest the name of RTG
carbenicillinases for this new enzyme group based on the unique RTG
triad. The first reference enzymes would be RTG-1 (
P. mirabilis GN79
-lactamase) and RTG-2 (CARB-5).
Nucleotide sequence accession number.
The
RTG-2/CARB-5 -lactamase sequence has been submitted to
GenBank. Its accession number is AF135373.
| |
ACKNOWLEDGMENTS |
We thank L. Gilly for her efficient technical help, F. Letourneur
(ICGM) for nucleotide sequencing, and C. Valencien
(INFOBIOGEN) and M. Assous for fruitful help and discussions
about phylogeny.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Laboratoire de
Biologie Moléculaire des Cellules Eucaryotes, UFR Cochin
Port-Royal 24, rue du Faubourg Saint-Jacques, 75014 Paris, France.
Phone: 00 33 1 44 41 23 47. Fax: 00 33 1 44 41 23 42. E-mail:
paul{at}citi2.fr.
| |
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Antimicrobial Agents and Chemotherapy, April 2000, p. 1070-1074, Vol. 44, No. 4
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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