Trade-offs between antibacterial resistance and fitness cost in the production of metallo-b-lactamases by enteric bacteria manifest as sporadic emergence of carbapenem resistance in a clinical setting

Meropenem is a clinically important antibacterial reserved for treatment of multiresistant infections. In meropenem-resistant bacteria of the family Enterobacterales, NDM-1 is considerably more common than IMP-1, despite both metallo-b-lactamases (MBLs) hydrolyzing meropenem with almost identical kinetics. We show that bla_NDM-1 consistently confers meropenem resistance in wild-type Enterobacterales, but bla_IMP-1 does not. The reason is higher bla_NDM-1 expression because of its stronger promoter. However, the cost of meropenem resistance is reduced fitness of bla_NDM-1-positive Enterobacterales. In parallel, from a clinical case, we identified multiple Enterobacter spp. isolates carrying a plasmid-encoded bla_NDM-1 having a modified promoter region. This modification lowered MBL production to a level associated with zero fitness cost, but, consequently, the isolates were not meropenem resistant. However, we identified a Klebsiella pneumoniae isolate from this same clinical case carrying the same bla_NDM-1 plasmid. This isolate was meropenem resistant despite low-level NDM-1 production because of a ramR mutation reducing envelope permeability. Overall, therefore, we show how the resistance/fitness trade-off for MBL carriage can be resolved. The result is sporadic emergence of meropenem resistance in a clinical setting.