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Resistance gene naming and numbering: is it a new gene or not?-authors' response.

Sir, We welcome the letter of Evans, which begins the conversation on resistance gene nomenclature in reply to our recent call for rationalization. Evans 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 Evans 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. 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. However, the upstream context of oxa23 is quite different from that of the intrinsic gene, which does not confer resistance. 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. 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. Evans 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.