Resistance to aztreonam in combination with non-β-lactam β-lactamase inhibitors due to the layering of mechanisms in Escherichia coli identified following mixed culture selection

Using mixed culture selection, we show how reduced envelope permeability, reduced target-site affinity, and increased β-lactamase production layer to confer aztreonam/β-lactamase inhibitor resistance in Escherichia coli. We report a clinical isolate producing CTX-M-15 and CMY-4, lacking OmpF, and carrying a PBP3 mutation. It is resistant to aztreonam plus the inhibitors avibactam, relebactam and vaborbactam. Mobilisation of bla SHV-12 into this isolate generated a derivative additionally resistant to aztreonam plus the bicyclic boronate inhibitors 2 and taniborbactam.