Vázquez-Ucha, Juan CarlosRodríguez, DianaLasarte-Monterrubio, CristinaLence, EmilioArca-Suárez, JorgeManeiro Rey, MaríaGato, EvaPérez, AstridMartínez Guitián, MartaJuan, CarlosOliver, AntonioBou, GermánGonzález-Bello, ConcepciónBeceiro Casas, Alejandro2026-05-192026-05-192021-04-29Vázquez-Ucha JC, Rodríguez D, Lasarte-Monterrubio C, Lence E, Arca-Suarez J, Maneiro M, Gato E, Perez A, Martínez-Guitián M, Juan C, Oliver A, Bou G, González-Bello C, Beceiro A. 6-Halopyridylmethylidene Penicillin-based sulfones efficiently inactivate the natural resistance of Pseudomonas aeruginosa to β-Lactam antibiotics. J Med Chem. 2021 May 13;64(9):6310-6328.1520-4804https://hdl.handle.net/2183/48300[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.engThis document is the Accepted Manuscript version of a Published Article that appeared in final form in Journal of Medicinal Chemistry, copyright © 2021 American Chemical Society. To access the final published article, see ACS Articles on Request.Immunity, InnatePenicillinsPseudomonas aeruginosaSulfonesbeta-Lactam Resistancejournal articleopen access10.1021/ACS.JMEDCHEM.1C00369