A kinetic analysis of the inhibition of FOX-4 β-lactamase, a plasmid-mediated AmpC cephalosporinase, by monocyclic β-lactams and carbapenems

Results: The Ki values for the monocyclicb-lactams against FOX-4b-lactamase were 0.04+0.01 mM (aztreonam) and 0.66+0.03 mM (BAL30072), and the Ki value for the bridged monobactam BAL29880 was 8.9+0.5 mM. For carbapenems, the Ki values ranged from 0.27+0.05 mM (ertapenem) to 2.3+0.3 mM (imipenem). ESI-MS demonstrated the formation of stable covalent adducts when the monocyclic b-lactams and carbapenems were reacted with FOX-4 b-lactamase. UVD spectroscopy suggested the appearance of different chromophoric intermediates. Conclusions: Monocyclic b-lactam and carbapenem antibiotics are effective mechanism-based inhibitors of FOX-4 b-lactamase, a clinically important pmAmpC, and provide stimulus for the development of new inhibitors to inactivate plasmidic and chromosomal class C b-lactamases.