Download Comment on: Resistance gene naming and

J Antimicrob Chemother 2016; 71: 1742 – 1745
doi:10.1093/jac/dkw037
Advance Access publication 6 March 2016
Comment on: Resistance gene naming
and numbering: is it a new gene or not?
Benjamin A. Evans*
Department of Biomedical and Forensic Sciences, Anglia Ruskin
University, East Road, Cambridge CB1 1PT, UK
*Corresponding author. Tel: +0845-196-2059;
E-mail: [email protected]
Sir,
In their recent Leading article, Hall and Schwarz1 state their intention
is to stimulate debate on how resistance genes should be named,
with a view to reaching an agreement that can be universally
applied. Debate on the classification of resistance genes has produced differences of opinion.2,3 Two obvious ways in which antibiotic
resistance genes can be named are either by their evolutionary
relatedness (i.e. sequence similarity) or by the functional similarities
of the gene products. Hall and Schwarz1 suggest that naming of
resistance genes should be based upon sequence similarity of either
the DNA or the predicted protein, and that a cut-off of ≥2% difference should be used to determine whether a new number should be
assigned (e.g. blaOXA-1, blaOXA-2 etc.), with variants differing by ,2%
given an additional secondary number (e.g. blaOXA-1-1, blaOXA-1-2
etc.). While I agree that numbering based upon sequence similarity
is a sensible suggestion, I do not believe a ≥2% cut-off value would
be appropriate. To illustrate this, of the 33 OXA-23-like b-lactamases
that have currently been identified and that are derived from the
same common source (the chromosome of Acinetobacter radioresistens),4 there is up to 8% difference in amino-acid sequence
between a given pair of sequences (B. A. Evans, unpublished data).
As such, under the proposed naming system, rather than all being
named blaOXA-23-1, blaOXA-23-2 etc., those that crossed the ≥2%
threshold would receive a completely new number. Thus, a ≥2%
cut-off would lead to an unwarranted proliferation of gene names.
In the same spirit for stimulating debate that Hall and Schwarz
used in their article,1 I suggest a modification of the system they
propose. Rather than a fixed numerical cut-off value for assignment of a new number, there should be an emphasis on considering these genes in context and their recent evolutionary history.
For example, intrinsic chromosomally carried genes can vary substantially but clearly belong to the same ‘group’ for naming purposes. On the other hand, mobilized genes are usually genetically
very similar due to their recent evolutionary bottleneck, and as
such it would be appropriate for them to belong to the same
named group. Variants that share the same recent history
would be assigned an additional secondary number, as Hall and
Schwarz1 suggest. It is clear there is much discussion to be had to
define this system. One suggestion is that an approach analogous
to that used for assigning new bacterial species names could be
considered, i.e. agreement by a resistance gene-naming committee. Such a system will require community effort to maintain, but
it would ensure that genes sharing common recent ancestry
would be grouped together, and it would be robust against the
future inevitable increase in genetic diversity in a way that a
fixed numerical cut-off would not be.
Alongside an agreed-upon numbering and naming system, it
is essential that an openly accessible database of resistance
genes that details the phenotype conferred by the gene is developed. Indeed, it could be argued that it is more important to
establish such a database than to renumber resistance genes
themselves, as a database would illustrate the similarities
between genes regardless of what they were called. An example
of such a database is being constructed by the National Center
for Biotechnology Information for b-lactamases (http://www.
ncbi.nlm.nih.gov/pathogens/submit_beta_lactamase/). As we
move into the era of bacterial genome sequencing in the clinic
for surveillance and diagnosis, it is essential that we have the
tools to tell us not just which allele of a particular resistance
gene an isolate has, but simultaneously what the implications
are for the isolate phenotype. The establishment and curation
of such a database will require ongoing funding and should be
identified as a priority area by science-funding councils.
Hall and Schwarz1 rightly highlight that as a community we
must debate and come to a conclusion on a common and sustainable system for gene naming that will cope with the explosion
in genome sequencing and thus identification of resistance gene
variants. While it is no small feat to overhaul and unify the disparate range of naming systems that currently exist, it is important
that we do so soon to maximize the use of these data both in
research and healthcare.
Funding
B. A. E. is supported by funds provided by Anglia Ruskin University.
Transparency declarations
None to declare.
References
1 Hall RM, Schwarz S. Resistance gene naming and numbering: is it a new
gene or not? J Antimicrob Chemother 2016; 71: 569– 71.
2 Giske CG, Sundsfjord AS, Kahlmeter G et al. Redefining extendedspectrum b-lactamases: balancing science and clinical need. J Antimicrob
Chemother 2009; 63: 1–4.
3 Bush K, Jacoby GA, Amicosante G et al. Comment on: Redefining
extended-spectrum b-lactamases: balancing science and clinical need.
J Antimicrob Chemother 2009; 64: 212–3; author reply 213–5.
# The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
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1742
JAC
Letters to the Editor
4 Poirel L, Figueiredo S, Cattoir V et al. Acinetobacter radioresistens as a
silent source of carbapenem resistance for Acinetobacter spp. Antimicrob
Agents Chemother 2008; 52: 1252 –6.
J Antimicrob Chemother 2016
doi:10.1093/jac/dkw126
Advance Access publication 13 April 2016
Resistance gene naming and numbering:
is it a new gene or not?—authors’
response
Ruth M. Hall1* and Stefan Schwarz2
1
School of Life and Environmental Sciences, The University of
Sydney, Sydney, 2006 New South Wales, Australia; 2Institute of
Farm Animal Genetics, Friedrich-Loeffler-Institut, Höltystr. 10,
31535 Neustadt-Mariensee, Germany
*Corresponding author. Tel: +61-2-9351-3465;
E-mail: [email protected]
Sir,
We welcome the letter of Evans,1 which begins the conversation
on resistance gene nomenclature in reply to our recent call for
rationalization.2 Evans1 agrees that change is needed, but questions the cut-off of ≥2% difference at the DNA (and protein)
level for assigning a new number as it ‘would lead to an unwarranted proliferation of gene names’. However, in the case of the
genes for OXA b-lactamases, the example used by Evans1 to illustrate the point, the current cut-off is a single basepair difference
(as long as it also produces an amino acid difference) and our cut-off
would in fact dramatically reduce the number of gene designations.
We agree that the context of a gene is important, particularly
when seeking gene origins. The origin and contexts of the oxa23
gene have been reviewed recently and the term oxa23, in line with
the original nomenclature for genes encoding class D oxacillinases, was used to refer to all variants.3 The oxa23 gene is one of
the genes responsible for carbapenem resistance in Acinetobacter
baumannii and other Acinetobacter species and is likely derived
from an intrinsic chromosomal gene in Acinetobacter radioresistens
that was recently designated oxaAr. 3 However, the upstream context of oxa23 is quite different from that of the intrinsic gene,
which does not confer resistance.3 The resistance gene, oxa23, is
expressed via a strong promoter supplied by an upstream IS, usually
ISAba1. We recently tabulated the differences between the 23
oxa23 variants listed in the database at http:/www.lahey.org (now
discontinued) that had been assigned a unique number.3 We found
no more than three differences (a single base difference or single
triplet insertion) from the original oxa23 sequence in any of them.
Four alleles of the oxaAr gene, each encoding a protein with a
different OXA number, were listed in the database, but sequence
was available for only one of them. It differed from oxa23 at 20
positions in a gene length of 822 bp (2.4%). However, the oxaAr
gene does not meet two of the criteria we proposed for inclusion
as a resistance gene, namely that intrinsic genes, i.e. those naturally found in a bacterial chromosome, should not be included
among the resistance genes, and that to be classified as a
resistance gene, resistance must be conferred. The oxaAr gene
is an intrinsic chromosomal gene found in A. radioresistens that,
in its natural context, does not confer antibiotic resistance.3,4
Evans1 raises the need for suitable databases, mentioning the
database we used, which has since been transferred to NCBI
(http:/www.ncbi.nlm.nih.gov/pathogens/submit_beta_lactamase/
studies/). We agree that repositories for named genes could be
useful. However, we point out that in the case of the oxa genes
encoding class D b-lactamases, this database is particularly problematic as it groups many quite different genes encoding proteins
sharing as little as 30% identity together. It does not give users an
indication of which specific gene a variant is related to or of the
relationships between often hundreds of gene variants that differ
by only a single basepair or a few basepairs. Allelic variants of
several intrinsic chromosomal genes are also included. As each
variant is given a number in order of submission as long as a single
basepair difference leads to an amino acid difference from one
of the main genes, this approach makes single genes appear to
be many. Hence, this database currently lacks the necessary utility
for the vast majority of researchers and for gene naming. Indeed,
the genes encoding OXA enzymes are in the most urgent need of
revision. The allelic variants of the intrinsic chromosomal genes,
which are used in strain typing applications, might usefully be
transferred to other databases such as the one holding the
MLST schemes of Acinetobacter or other species.
Transparency declarations
None to declare.
References
1 Evans BA. Comment on: Resistance gene naming and numbering: is it a
new gene or not? J Antimicrob Chemother 2016; 71:1742 –3.
2 Hall RM, Schwarz S. Resistance gene naming and numbering: is it a new
gene or not? J Antimicrob Chemother 2016; 71: 569– 71.
3 Nigro SJ, Hall RM. Structure and context of Acinetobacter transposons
carrying the oxa23 carbapenemase gene. J Antimicrob Chemother
2016; 71: 1135 – 47.
4 Poirel L, Figueiredo S, Cattoir V et al. Acinetobacter radioresistens as a
silent source of carbapenem resistance for Acinetobacter spp. Antimicrob
Agents Chemother 2008; 52: 1252 –6.
J Antimicrob Chemother 2016
doi:10.1093/jac/dkw034
Advance Access publication 8 March 2016
Comment on: Mortality due to blaKPC
Klebsiella pneumoniae bacteraemia
Daniele Roberto Giacobbe1*, Mario Tumbarello2,
Valerio Del Bono1 and Claudio Viscoli1 on behalf of ISGRISITA (Italian Study Group on Resistant Infections of the
Società Italiana Terapia Antinfettiva)
1
Infectious Diseases Unit, University of Genoa (DISSAL) and IRCCS
San Martino-IST, Genoa, Italy; 2Institute of Infectious Diseases,
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