Discovery of Quercetin and Its Analogs as Potent OXA-48 Beta-Lactamase Inhibitors

Carbapenem resistance in Enterobacteriaceae caused by OXA-48 beta-lactamase is a growing global health threat and has rapidly spread in many regions of the world. Developing inhibitors is a promising way to overcome antibiotic resistance. However, there are few options for problematic OXA-48. Here we identified quercetin, fisetin, luteolin, 3',4',7-trihydroxyflavone, apigenin, kaempferol, and taxifolin as potent inhibitors of OXA-48 with IC50 values ranging from 0.47 to 4.54 mu M. Notably, the structure-activity relationship revealed that the substitute hydroxyl groups in the A and B rings of quercetin and its structural analogs improved the inhibitory effect against OXA-48. Mechanism studies including enzymatic kinetic assay, isothermal titration calorimetry (ITC), and surface plasmon resonance (SPR) analysis demonstrated that quercetin reversibly inhibited OXA-48 through a noncompetitive mode. Molecular docking suggested that hydroxyl groups at the 3', 4' and 7 positions in flavonoids formed hydrogen-bonding interactions with the side chains of Thr209, Ala194, and Gln193 in OXA-48. Quercetin, fisetin, luteolin, and 3',4',7-trihydroxyflavone effectively restored the antibacterial efficacy of piperacillin or imipenem against E. coli producing OXA-48, resulting in 2-8-fold reduction in MIC. Moreover, quercetin combined with piperacillin showed antimicrobial efficacy in mice infection model. These studies provide potential lead compounds for the development of beta-lactamase inhibitors and in combination with beta-lactams to combat OXA-48 producing pathogen.

Automated summary

Carbapenem resistance caused by OXA-48 beta-lactamase is a global health threat. In this study, quercetin and its analogs were identified as potent inhibitors of OXA-48, with the ability to restore the antibacterial efficacy of certain antibiotics against OXA-48-producing bacteria. Mechanism studies revealed that these compounds interacted with OXA-48 through hydrogen bonding, leading to the inhibition of its activity. Additionally, quercetin showed antimicrobial activity in combination with certain antibiotics in a mouse infection model.