Genesis of BRO β‐lactamase‐producing Moraxella catarrhalis: evidence for transformation‐mediated horizontal transfer

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Abstract
The dramatic rise in BRO‐producing M. catarrhalis strains observed in the last decades is without precedence. The aim of this study was to elucidate the events that led to the emergence of BRO‐1 and BRO‐2 β‐lactamases. Previously, we showed bro1 and bro2 to be >99% identical. Data presented here suggested that bro2 was acquired by a fortuitous event and inserted between M. catarrhalis genes orf1 and orf3. Subsequently, bro1 evolved from bro2. Promoter‐up mutations increased fitness of bro2, explaining its present predominance. The highly conserved nature of bro compared with orf1 and orf3 suggested that acquisition has occurred relatively recently. The random distribution of bro among M. catarrhalis fingerprint types indicated that bro has spread by horizontal transfer. Sequence analysis revealed that 80–200 bp is generally cotransferred with bro, serving as regions of homology that target bro to the same chromosomal locus. A region of 160 bases upstream of bro1 lacked polymorphism, indicating it was derived from the original strain that acquired bro2. We observed that bro was readily transferred by transformation between M. catarrhalis strains in vitro, suggesting a mechanism by which bro has disseminated. In conclusion, we have been able to reconstruct the steps that led to the emergence of BRO‐producing M. catarrhalis.