6-Halopyridylmethylidene Penicillin-Based Sulfones Efficiently Inactivate the Natural Resistance of Pseudomonas aeruginosa to β-Lactam Antibiotics

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Abstract

Pseudomonas aeruginosa, 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 1-3 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 ampC 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 2 was the inhibitor with the lowest KI (15.6 nM) and the highest inhibitory efficiency (kinact/KI). Computational studies using diverse AmpC enzymes revealed that the aromatic moiety in 1-3 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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Vázquez-Ucha, J. C., Rodríguez, D., Lasarte-Monterrubio, C., Lence, E., Arca-Suarez, J., Maneiro, M., … Beceiro, A. (2021). 6-Halopyridylmethylidene Penicillin-Based Sulfones Efficiently Inactivate the Natural Resistance of Pseudomonas aeruginosa to β-Lactam Antibiotics. Journal of Medicinal Chemistry, 64(9), 6310–6328. https://doi.org/10.1021/acs.jmedchem.1c00369

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