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Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, May 2005, p. 2148-2150, Vol. 49, No. 5
0066-4804/05/$08.00+0 doi:10.1128/AAC.49.5.2148-2150.2005
Nomenclature of GES-Type Extended-Spectrum ß-Lactamases
 |
LETTER
|
|---|
In
two recently published articles, Wachino et al. designated a
novel ceftazidime-hydrolyzing class A extended-spectrum
ß-lactamase (ESBL) (GES-a) as GES-3
(4), and a new
cephamycin-hydrolyzing and inhibitor-resistant class A ESBL
(GES-b) as GES-4
(5). In actuality, their
articles are fraught with misleading nomenclature of GES-type ESBLs and
controvertible conclusions on the relationship between
ß-lactamase inhibitor resistance and an amino acid substitution
in the center of the 
-loop region.
Before Wachino and
colleagues submitted their sequences for GES-a and GES-b genes to the
GenBank nucleotide databank (release dates, 25 May 2004 and 28 July
2004, respectively), sequences for GES-3 and GES-4 genes had already
been released by Vourli et al.
(3), the release date of
which was 12 May 2004. As shown in Table
1, GES-a and GES-b genes are completely different from GES-3 and GES-4
genes. GES-3 and GES-4 were capable of hydrolyzing imipenem
(3), while GES-a could not
hydrolyze imipenem and GES-b had a substrate profile extended to
cephamycins as well as imipenem
(4,
5). Presently, the
different GES-type ESBLs have been designated by identical names. On
the basis of priority of nomenclature, GES-a and GES-b genes should be
renamed as GES-5 and GES-6 genes, respectively.
In their efforts
to persuade readers that GES-b has a strong inhibitor-resistant nature
like IRT enzymes and that it maintains the capacity to hydrolyze
cephamycins and imipenem as a result of a single substitution at
position 170, the center of the -loop region, Wachino et al.
(5) stated: "In
comparison with GES-1, GES-2 [containing a single substitution at
position 170] showed an extended substrate specificity for
imipenem and a lower affinity for ß-lactamase inhibitors
(1), as was seen with
GES-4 [GES-b]." However, Poirel et al.
(1) stated:
"Inhibition studies as measured by IC50s with
benzylpenicillin as a substrate showed that GES-2 activity was
inhibited by clavulanic acid and tazobactam more than GES-1
is." The IC50s (inhibitory concentrations) of
clavulanic acid and tazobactam for GES-b (15.2 and 1.43 µM,
respectively) were higher than those of GES-1 (5 and 2.5 µM,
respectively), GES-2 (1 and 0.5 µM, respectively), and GES-a
(1.5 and 0.19 µM, respectively). Two GES-type ESBLs (GES-2 and
GES-b) containing a single substitution at position 170 showed a
different inhibition profile. Although GES-b has a strong
inhibitor-resistant nature like IRT enzymes, the conclusion that the
G170S substitution found in the GES-b affected inhibitor resistance
could not be supported by the data as presented.
The renaming of
GES-a and GES-b can help some authors to correctly designate new
GES-type ESBLs, such as the novel enzymes identified from our
nationwide survey supported by the Korea Research Foundation
(KRF-2004-042-E00117).
|
REFERENCES
|
|---|
- Poirel,
L., G. F. Weldhagen, T. Naas, C. D. Champs,
M. G. Dove, and P. Nordmann. 2001. GES-2, a
class A ß-lactamase from Pseudomonas aeruginosa with
increased hydrolysis of imipenem. Antimicrob. Agents
Chemother.
45:2598-2603.[Abstract/Free Full Text]
- Poirel,
L., I. L. Thomas, T. Naas, A. Karim, and P. Nordmann.2000
. Biochemical sequence analyses of GES-1, a noble
class A extended-spectrum ß-lactamase, and the class 1 integron
IN52 from Klebsiella pneumoniae. Antimicrob.
Agents Chemother.
44:622-632.[Abstract/Free Full Text]
- Vourli,
S., P. Giakkoupi, V. Miriagou, E. Tzelepi, A. C. Vatopoulos,
and L. S. Tzouvelekis. 2004. Novel GES/IBC
extended-spectrum ß-lactamase variants with carbapenemase
activity in clinical enterobacteria. FEMS Microbiol.
Lett.
234:209-213.[Medline]
- Wachino,
J.-I., Y. Doi, K. Yamane, N. Shibata, T. Yagi, T. Kubota, H. Ito, and
Y. Arakawa. 2004. Nosocomial spread of
ceftazidime-resistant Klebsiella pneumoniae strains producing
a novel class A ß-lactamase, GES-3, in a neonatal intensive
care unit in Japan. Antimicrob. Agents Chemother.
48:1960-1967.[Abstract/Free Full Text]
- Wachino,
J.-I., Y. Doi, K. Yamane, N. Shibata, T. Yagi, T. Kubota, and Y.
Arakawa. 2004. Molecular characterization of a
cephamycin-hydrolyzing and inhibitor-resistant class A
ß-lactamase, GES-4, possessing a single G170S substitution on
the -loop. Antimicrob. Agents Chemother.
48:2905-2910.[Abstract/Free Full Text]
| | | | | |
Sang Hee Lee*
Department of Biological Sciences
Myongji University
San 38-2 Namdong
Yongin, Kyunggido 449-728
Republic of Korea
Seok Hoon Jeong
Department of Laboratory Medicine
College of Medicine
Kosin University
Busan 602-702
Republic of Korea
|
| | | | | |
* Phone: 82 31 330 6195
Fax: 82 31 335 8249
E-mail: sangheelee{at}mju.ac.kr. |
Authors' Reply 1
|
LETTER
|
|---|
Unfortunate
confusions in the nomenclature or the numbering of antibiotic
resistance genes have occurred in various papers to date. In fact,
several duplicate gene names have been sometimes assigned to the same
resistance gene. In addition, dissimilar resistance genes possessing
different nucleotide sequences have been assigned the same gene number.
To solve these problems and resolve ambiguity, some useful suggestions
have been made and discussed so far
(1).
The dates of
data submission to the GenBank/EMBL/DDBJ and data release as well as
the review and publication periods were involved in the confusion that
has occurred in the designated nomenclature of GES-3 and GES-4
beta-lactamases
(4-6).
For example, as shown in Table
2, we submitted our
sequence data for GES-3 and GES-4 to the GenBank/EMBL/DDBJ earlier than
S. Vourli et al. Moreover, our manuscripts have also been submitted to
the American Society for Microbiology earlier than theirs. Thus, we are
persuaded that the priority of gene names should depend solely on the
deposition date of the DNA sequence to the database and the submission
date of the manuscripts to the relevant publication offices. For their
part, Drs. Hall, Partridge, et al. recommended that the gene name
assignment should depend, rather, on the date of data release by the
GenBank/EMBL/DDBJ database
(1). At any rate, it
would seem that this kind of confusion is unavoidable under the current
systems employed for data deposition, data release, manuscript review,
and publication. As a possible solution to this kind of confusion, the
assignment of all antibiotic resistance gene names should be controlled
through a web site such as
http://www.lahey.org/studies/webt.htm,
as was proposed by Hall et al.
(1). Moreover, to resolve
the confusion among GES-3 and GES-4 beta-lactamases, we would like to
propose here a practical modification in the naming of GES-3 and GES-4
enzymes (Table
2).
In our previous article
(5), we stated as
follows: "In comparison with GES-1, GES-2 showed an extended
substrate specificity for imipenem and a lower affinity for
ß-lactamase inhibitors, as was seen with GES-4." As was
suggested by Drs. Lee and Jeong, this sentence might indeed cause some
misunderstanding about the properties of GES-type enzymes against
beta-lactamase inhibitors. However, since the IC50s of
clavulanic acid for various TEM-derived ESBLs are usually lower than
0.2 µM/ml, our actual meaning could be further clarified by
adding the following: "Among class A enzymes, GES enzymes,
including GES-2, generally demonstrate lower affinities for
beta-lactamase inhibitors."
The above investigators
mentioned that the G170S substitution found in GES-4J could not
sufficiently explain the inhibitor-resistant nature of
GES-4J. In our article
(5), we compared the
inhibition properties under the same experimental conditions between
our GES-3J and those of GES-4J possessing a single G170S substitution.
Although the IC50 of clavulanic acid for GES-2 (which has a
single G170N substitution compared with GES-1
[2]) was lower
than that for GES-1 (3),
the G170S substitution found in GES-4J apparently served to raise the
resistance level against beta-lactamase inhibitors
(5). The differences
observed in the substrate specificities and inhibition properties among
GES-1, GES-2, GES-3G, GES-4G, GES-3J, and GES-4J enzymes must be
attributable to the amino acid substitution at position 170 as well as
those at positions 62 or 104. In any event, it is probable that the
amino acid substitution at position 170 plays a key role in the
expansion of substrate specificity among GES-type beta-lactamases, as
has been demonstrated in the cases of GES-2 and GES-4J. Further
enzymological analyses of GES-3G and GES-4G will reinforce our
speculation, since both enzymes have a G170S substitution like the one
in GES-4J. Molecular modeling analysis as well as a detailed X-ray
crystallographic analysis will well explain the role of the amino acid
substitution at position 170 in GES-type beta-lactamases. Both analyses
will be undertaken in our forthcoming
study.
|
REFERENCES
|
|---|
- Hall,
R., S. Partridge, P. A. Bradford, K. Bush, G. A.
Jacoby, L. B. Rice, and L. S. Young.2003
. Unambiguous numbering of antibiotic resistance
genes. Antimicrob. Agents Chemother.
47:3998-3999.[Free Full Text]
- Poirel,
L., I. Le Thomas, T. Naas, A. Karim, and P. Nordmann.2000
. Biochemical sequence analyses of GES-1, a novel
class A extended-spectrum ß-lactamase, and the class 1 integron
In52 from Klebsiella pneumoniae. Antimicrob. Agents
Chemother.
44:622-632.
- Poirel,
L., G. F. Weldhagen, T. Naas, C. De Champs, M. G.
Dove, and P. Nordmann. 2001. GES-2, a class A
ß-lactamase from Pseudomonas aeruginosa with increased
hydrolysis of imipenem. Antimicrob. Agents Chemother.
45:2598-5603.
- Vourli,
S., P. Giakkoupi, V. Miriagou, E. Tzelepi, A. C. Vatopoulos,
and L. S. Tzouvelekis. 2004. Novel GES/IBC
extended-spectrum beta-lactamase variants with carbapenemase activity
in clinical enterobacteria. FEMS Microbiol. Lett.
234:209-213.
- Wachino,
J.-I., Y. Doi, K. Yamane, N. Shibata, T. Yagi, T. Kubota, and Y.
Arakawa. 2004. Molecular characterization of a
cephamycin-hydrolyzing and inhibitor-resistant class A
ß-lactamase, GES-4, possessing a single G170S substitution in
the -loop. Antimicrob. Agents Chemother.
48:2905-2910.
- Wachino,
J.-I., Y. Doi, K. Yamane, N. Shibata, T. Yagi, T. Kubota, H. Ito, and
Y. Arakawa. 2004. Nosocomial spread of
ceftazidime-resistant Klebsiella pneumoniae strains producing
a novel class A ß-lactamase, GES-3, in a neonatal intensive
care unit in Japan. Antimicrob. Agents Chemother.
48:1960-1967.
| | | | | |
Jun-ichi Wachino and
Yoshichika Arakawa*
Department of Bacterial Pathogenesis and Infection Control
National Institute of Infectious Diseases
4-7-1 Gakuen, Musashi-Murayama
Tokyo 208-0011, Japan
|
| | | | | |
* Phone: 81-42-561-0771, ext. 500
Fax: 81-42-561-7173
E-mail: yarakawa{at}nih.go.jp. |
Authors' Reply 2
|
LETTER
|
|---|
This comment
is an attempt to rectify several mistakes in the nomenclature of
GES-type enzymes and some false comments written in recently published
papers on the subject. This initiative is relevant since it is true
that some confusion has appeared in that field and, worse, that some
false information has been reported. It is noteworthy that this enzyme
(originally detected in a Klebsiella pneumoniae isolate from
French Guiana and thus named GES for Guiana-Extended-Spectrum
ß-lactamase) is widespread in view of the recently published
studies. ß-Lactamase GES-1 and variants have been identified in
Europe (France, Portugal, Greece) and also in South Africa, Brazil, and
Japan in several species, including spp. of Enterobacteriaceae
and Pseudomonas aeruginosa. The origin of these
ß-lactamase genes remains unknown. It is correct to underline
that GES-2, the first described ESBL with such a capacity to hydrolyze
imipenem, is well inhibited by ß-lactamase inhibitors. In terms
of nomenclature, an update is required, since identical names have been
given for different enzymes which possess different hydrolytic
properties. However, the authors did not include in their update the
IBC-1 and IBC-2 enzymes which are also just point mutant
analogues of the GES enzymes. To clarify the situation, we propose to
maintain the current denomination concerning the fully characterized
GES-3 and GES-4 enzymes published by Wachino et al. (references 4 and 5
of the comment letter above) and to rename the variants published by
Vourli et al. as GES-5 and GES-6 (for GES-3 and GES-4,
respectively). Therefore, the IBC-1 and IBC-2 variants identified in
Greece (1,
2) should be renamed
GES-7 and GES-8,
respectively.
|
REFERENCES
|
|---|
- Giakkoupi,
P., L. S. Tzouvelekis, A. Tsakris, V. Loukova, D. Sofianou,
and E. Tzelepi. 2000. IBC-1, a novel
integron-associated class A ß-lactamase with extended-spectrum
properties produced by an Enterobacter cloacae clinical
strain. Antimicrob. Agents Chemother.
44:2247-2253.[Abstract/Free Full Text]
- Mavroidi,
A., E. Tzelepi, A. Tsakris, V. Miriagou, D. Sofianou, and L.
S. Tzouvelekis. 2001. An integron-associated
ß-lactamase (IBC-2) from Pseudomonas aeruginosa is a variant of
the extended-spectrum ß-lactamase IBC-1. J.
Antimicrob. Chemother.
48:627-630.[Abstract/Free Full Text]
| | | | | |
L. Poirel
P. Nordmann
Service de Bactériologie-Virologie
Université Paris XI
Hôpital de Bicêtre
Assistance Publique/Hôpitaux de Paris
Faculté de Médecine Paris-Sud
94275 Le K.-Bicêtre, France
|
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Antimicrobial Agents and Chemotherapy, May 2005, p. 2148-2150, Vol. 49, No. 5
0066-4804/05/$08.00+0 doi:10.1128/AAC.49.5.2148-2150.2005
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