An updated phylogeny of the metallo-β-lactamases

Abstract

Abstract Background Metallo-β-lactamases (MBLs) are enzymes that use zinc-dependent hydrolysis to confer resistance to almost all available β-lactam antibiotics. They are hypothesized to originate from commensal and environmental bacteria, from where some have mobilized and transferred horizontally to pathogens. The current phylogeny of MBLs, however, is biased as it is founded largely on genes encountered in pathogenic bacteria. This incompleteness is emphasized by recent findings of environmental MBLs with new forms of zinc binding sites and atypical functional profiles. Objectives To expand the phylogeny of MBLs to provide a more accurate view of their evolutionary history. Methods We searched more than 16 terabases of genomic and metagenomic data for MBLs of the three subclasses B1, B2 and B3 using the validated fARGene method. Predicted genes, together with the previously known ones, were used to infer phylogenetic trees. Results We identified 2290 unique MBL genes forming 817 gene families, of which 741 were previously uncharacterized. MBLs from subclasses B1 and B3 separated into distinct monophyletic groups, in agreement with their taxonomic and functional properties. We present evidence that clinically associated MBLs were mobilized from Proteobacteria. Additionally, we identified three new variants of the zinc binding sites, indicating that the functional repertoire is broader than previously reported. Conclusions Based on our results, we recommend that the nomenclature of MBLs is refined into the phylogenetic groups B1.1–B1.5 and B3.1–B3.4 that more accurately describe their molecular and functional characteristics. Our results will also facilitate the annotation of novel MBLs, reflecting their taxonomic organization and evolutionary origin.