, a major cause of nosocomial infections, is considered a paradigm of antimicrobial resistance, largely due to hyperproduction of chromosomal cephalosporinase AmpC. Here, we explore the ability of 6-pyridylmethylidene penicillin-based sulfones to inactivate the AmpC β-lactamase and thus rescue the activity of the antipseudomonal ceftazidime. These compounds increased the susceptibility to ceftazidime in a collection of clinical isolates and PAO1 mutant strains with different expression levels and also improved the inhibition kinetics relative to avibactam, displaying a slow deacylation rate and involving the formation of an indolizine adduct. Bromide was the inhibitor with the lowest (15.6 nM) and the highest inhibitory efficiency (/). Computational studies using diverse AmpC enzymes revealed that the aromatic moiety in targets a tunnel-like site adjacent to the catalytic serine and induces the folding of the H10 helix, indicating the potential value of this not-always-evident pocket in drug design.
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