Meropenem selection induced overproduction of the intrinsic carbapenemase as well as phenotype divergence in Acinetobacter baumannii

- Subinhibitory concentration of meropenem can induce phenotype divergence and carbapenem resistance in A. baumannii.
- Two types of resistant mutants were obtained, showing differences in multiple phenotypes.
- Both mutants activated intrinsic blaOXA-508 expression to confer major carbapenem resistance.
- OXA-508 is a new member of OXA-51-like, showing potential preference for meropenem.
- Meropenem exposure induced the site-specific transposition of ISAba1 to blaOXA-51-like.

Acinetobacter baumannii 37662 is a carbapenem-susceptible isolate with blaOXA-51-like as the sole carbapenemase gene. Following selection with meropenem (MEM) at a subinhibitory concentration, two morphologically different mutants, designated 37662RM1 and 37662RM2, were obtained and characterised. Compared with the parent strain, resistant mutant 37662RM1 grew at a slower rate and had impaired capsule synthesis, whereas 37662RM2 grew fast and abolished capsule synthesis. In addition, the latter resistant mutant also lost pathogenicity but showed significantly enhanced biofilm formation. Transposition of the insertion sequence ISAba1 and formation of ISAba1-blaOXA-51-like was responsible for the upregulated expression of blaOXA-51-like. The blaOXA-51-like gene of A. baumannii 37662 is a close variant of blaOXA-138 and has been designated blaOXA-508. Overproduction of OXA-508 conferred major carbapenem resistance to these two mutants. Overall, these results indicate that a subinhibitory concentration of MEM can induce phenotype divergence together with carbapenem resistance in A. baumannii.