The conundrum of naming resistance gene determinants

Sir,

I read with great interest the Leading article by Hall and Schwarz¹ and the comments by Evans² and Jacoby et al.³ regarding the ongoing debate on how resistance genes should be named such that the nomenclature is universally acceptable. Although I agree that numbering based upon sequence similarity is a sensible suggestion by Hall and Schwarz,¹ I couldn’t agree more with the point of Evans,² who suggests that a ≥2% cut-off value would not be appropriate in naming a particular gene. Firstly, I would like to point out that we need to work on a foundation that has been built rather than destroying it and starting all over again.

As Evans² suggests, there should be an emphasis on considering genes in context and their recent evolutionary history, and for that he points out that the variation in intrinsic chromosomally carried genes can vary substantially but clearly belong to the same ‘group’ for naming purposes and should be given secondary numbers. This is a good idea, but not so good if a plasmid-encoded determinant was to move onto the chromosome, leading to clonal expansion. An example of this is the clonal spread of chromosomal tet(O) determinants, which has been observed in Campylobacter spp. (B. S. Lopes, unpublished data). Evans² also suggests that mobilized genes are usually genetically very similar and as such it would be appropriate for them to belong to the same named group. While this is a sensible suggestion, we need to understand the spread of determinants in different species of bacteria and broaden our views so that they can be applicable to other bacterial species.

The numerical system developed by Jacoby and Bush should still be considered as the gold standard for naming resistance determinants as it is easily to follow, less confusing and widely acceptable worldwide. It depends on assigning a number to a variant if a single amino-acid change occurs at the protein level. This is appropriate because it doesn’t allow naming of variants (e.g. OXA-65, OXA-193) that have SNPs at the nucleotide level, but are identical at the protein level. Naming variants differing at the nucleotide level that are 100% identical at the protein level could be useful, as it may offer insights into evolutionary relationships of specific OXA lineages. The Jacoby and Bush numbering system is unique and helps us to delineate specific variants that group together in certain species (e.g. OXA-51 and its variants in Acinetobacter baumannii or OXA-23 and its variants in Acinetobacter spp.). I believe that naming oxa-23 as oxaAr⁴ simply complicates matters further, a phenomenon that we see when using the terms bla_OXA-23 and bla_ARI-1, which are different names for the same gene.⁵ Furthermore, I don’t believe that numerical numbering should be replaced with assigning gene names with initials of bacterial species, which has been seen recently.⁴ For instance, while oxaAr refers to oxacillinase belong to Acinetobacter radioresistens, it could easily be confused with OXA from Acinetobacter rudis if we were to discover OXA-23 determinants in the latter species. More importantly this is something that will confuse researchers and clinicians who are new to the field and trying to understand the resistance determinant nomenclature.

Nigro and Hall⁴ discuss the OXA-23 variants and highlight that certain oxacillinases, such as OXA-49 and OXA-146, have proteins made up of 274 amino acids rather than 273 as encoded by bla_OXA-23. This phenomenon also occurs in Campylobacter and is due to the evolvability of oxacillinase in a specific niche environment. The intrinsic Campylobacter oxacillinases belong to OXA-61-like⁶ (OXAs 193, 450, 451, 452, 453, 460, 461, 489) or OXA-184-like (OXAs 185, 446, 447, 448, 449, 466) families. OXA-446 is similar to OXA-447 except that OXA-447 has an extra NNRIKSFY sequence at the C-terminal end. A similar phenomenon is seen in OXA-448 and OXA-449, which share amino-acid similarity for the first 243 amino acids, but with OXA-448 having IYSLN and OXA-449 having LAIITN at the C-terminal end. Another striking difference is between bla_OXA-460/461 and bla_OXA-61 genes found in Campylobacter spp., which belong to the OXA-61-like family, the difference being that bla_OXA-460/461 encodes 253 amino acids, whereas bla_OXA-61 encodes 257 amino acids. It is noteworthy to consider OXA-460/461 as more recently evolved enzymes because it has been shown that certain extreme environmental conditions/ecological adaptations can account for the shorter length of genetic determinants.⁷ Hence, it is important to consider various factors that shape the evolution of resistance determinants, rather than limiting our view to the notion of a fixed cut-off value. This flexibility is allowed when assigning an allele number to MLST loci that are variable in length in certain species of bacteria, such as Campylobacter (gltA, 399–402 bp), and it should be allowed for naming resistance variants as well. I also believe that it is important to focus on other bacterial species that harbour intrinsic oxacillinases (e.g. Campylobacter spp., OXA-61 and other groups of OXA; B. S. Lopes, unpublished data) and have a broader view of classification, which Hall and Schwarz⁸ fail to address. This is essential in order to increase our understanding of antibiotic resistance mechanisms and indeed evolution of resistance genes.

The community has a responsibility to make science simple and accessible to new researchers and clinicians in order to further our understanding of antimicrobial resistance determinants. This is only possible by working on a foundation that has been already built rather than starting anew. The simplicity of naming resistance gene determinants will not only help in maintaining the interest of early-career academics and clinicians in understanding antimicrobial resistance determinants, but also encourage more research into the evolution of resistance genes.

Transparency declarations

None to declare.

Acknowledgements

This letter is dedicated to the hard work of Karen Bush and George Jacoby and their team, who have worked relentlessly in assigning numbers to β-lactamase variants since 1997.

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