oxaAb are intrinsic to A. baumannii

OXA-type beta-lactamases are found in many bacterial species and comprise the largest family of beta-lactamases (Yoon and Jeong, 2021). It is thought that all members of the Acinetobacter genus carry the gene for an OXA-type beta-lactamase on their chromosome. More specifically, each Acinetobacter species has a distinct OXA-type beta-lactamase that is characteristic of the species. In the case of A. baumannii, this is the OxaAb (or OXA-51-like) beta-lactamase. 

Nomenclature

The nomenclature of OXA-type beta-lactamases, which belong to the class D beta-lactamases, is based upon the principle that each different amino-acid sequence is given a new allele number in a purely sequential manner, irrespective of whether these alleles derive from the same gene or not. The first intrinsic OXA beta-lactamase gene identified in A. baumannii was therefore named bla_OXA-51 following this naming convention (Brown, Young and Amyes, 2005). As the number of different alleles for this gene increased, the term bla_OXA-51-like was adopted to describe the group of alleles.

 

Some authors have recently started referring to the OXA-51-like enzymes as the OxaAb enzymes, and the bla_OXA-51-like genes as oxaAb genes, with the ‘Ab’ signifying that these are the OXA beta-lactamases intrinsic to A. baumannii (Nigro and Hall, 2016; Nigro and Hall, 2018; Takebayashi et al., 2021). The allele for the gene is then given in parenthesis e.g. oxaAb(51) is the same as bla_OXA-51. It is proposed that this system preserves the information regarding the specific allele while simultaneously identifying the specific gene the alleles belong to. This allows easy distinction between these alleles and those belonging to other OXA beta-lactamases found both various Acinetobacter species and in other genera. Both of these nomenclatures are currently used in the literature.

The number of oxaAb alleles that have been identified has rapidly increased, and currently numbers more than 370 alleles. These can be viewed in the NCBI Bacterial Antimicrobial Resistance Reference Gene Database (Reference Gene Catalog - Pathogen Detection - NCBI (nih.gov)).

Association with epidemic lineages

As the oxaAb gene is an intrinsic chromosomal gene in A. baumannii, much of the allelic diversity reflects the population structure of the species, with different alleles being representative of different bacterial lineages. A clear example of this is found with the international clones (ICs), also referred to as global clones (GCs), where a specific oxaAb allele is associated with the clone (Table 1).

Role in antimicrobial resistance

A small number of OxaAb enzymes have been purified and their kinetics measured to determine the ability to hydrolyse beta-lactam antibiotics. OxaAb enzymes are able to hydrolyse penicillins but generally not cephalosporins. While it is thought most OxaAb variants are not particularly effective at hydrolysing clinically used carbapenem antibiotics, a few variants with amino acid substitutions at particular sites (e.g. positions 129, 130, 167, 222) appear to be able to hydrolyse carbapenems, and in one instance, late generation cephalosporins (Brown, Young and Amyes, 2005; Héritier et al., 2005; Zander et al., 2013; Mitchell and Leonard, 2014; Schroder et al., 2016; Takebayashi et al., 2021; Chan et al., 2022). 

The crystal structures of OxaAb(51) and OxaAb(66) have been solved (Figure 1) (Smith et al., 2015; June et al., 2016; Takebayashi et al., 2022). Analyses of the amino acid positions listed above confirmed their involvement in altering the activity of the enzyme through altering the environment of the active site and facilitating greater access for the antibiotics (Figure 2).

A. baumannii is able to drive increased expression levels of the oxaAb genes through the integration of insertion sequences (IS) upstream of the oxaAb gene. Here, the IS provides a strong promotor that drives increased expression of this gene (Figure 3) (Turton et al., 2006; Figueiredo et al., 2009a). By far the most common IS that does this is ISAba1. In a few rare instances, IS elements have been found to insert into the oxaAb gene, inactivating it.

It has been noted that the frequency of oxaAb alleles that can be found with an IS element upstream of them is not equal across all alleles. The alleles that encode OxaAb variants with mutations at amino acid positions that increase the carbapenemase activity of the enzymes as described above are more often found to have an ISAba1 element upstream than other alleles that do not effectively hydrolyse carbapenems (Evans et al., 2008).

Evolution of the oxaAb genes

While much of the diversity observed in oxaAb alleles likely reflects the underlying genetic diversity of the species, there is evidence that certain alleles have arisen due to antibiotic selective pressure. Enzyme variants with differences at amino acid sites known to be responsible for increasing the ability of the enzymes to hydrolyse carbapenems appear to have been selected for on multiple occasions as they arise in many separate enzyme variants across the phylogenetic tree (Figure 4).

Mobilised oxaAb genes

While the oxaAb genes are normally chromosomally located, there have been rare reports of the gene being located on a plasmid. To date these have been from Taiwan. Plasmids carrying oxaAb were found in Acinetobacter nosocomialis and Acinetobacter seifertii (Lee et al., 2009; Chen et al., 2010; Lee et al., 2012; Li et al., 2021). The oxaAb gene appears to have been mobilised onto plasmids via ISAba1-mediated single-ended transposition. The reason why these plasmids have only been observed in Taiwan to date is unclear. Unlike some other OXA-type enzymes such as Oxa23, it is very rare for oxaAb genes to be located in a composite transposon, which may have contributed to their limited spread outside of A. baumannii.

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