Taxifolin as a Metallo-β-Lactamase Inhibitor in Combination with Augmentin against Verona Imipenemase 2 Expressing Pseudomonas aeruginosa

Abstract

Among the various mechanisms that bacteria use to develop antibiotic resistance, the multiple expression of β-lactamases is particularly problematic, threatening public health and increasing patient mortality rates. Even if a combination therapy—in which a β-lactamase inhibitor is administered together with a β-lactam antibiotic—has proven effective against serine-β-lactamases, there are no currently approved metallo-β-lactamase inhibitors. Herein, we demonstrate that quercetin and its analogs are promising starting points for the further development of safe and effective metallo-β-lactamase inhibitors. Through a combined computational and in vitro approach, taxifolin was found to inhibit VIM-2 expressing P. aeruginosa cell proliferation at <4 μg/mL as part of a triple combination with amoxicillin and clavulanate. Furthermore, we tested this combination in mice with abrasive skin infections. Together, these results demonstrate that flavonol compounds, such as taxifolin, may be developed into effective metallo-β-lactamase inhibitors.