Quercetin inhibits carbapenemase and efflux pump activities among carbapenem-resistant Gram-negative bacteria

Rapid dissemination of carbapenem-resistant Gram-negative bacteria (CRGNB) is a global threat. Quercetin is known for its antimicrobial activity. In this study, carbapenemase and efflux pump inhibitory activities of quercetin were demonstrated against carbapenem-resistant Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii. Further, molecular docking was performed to elucidate molecular mechanisms of such inhibition. CRGNB, expressing one of the carbapenemases, demonstrated significant inhibition of carbapenemase activity when pre-incubated with 64 mu g/ml quercetin. Moreover, acrB overexpressing enterobacterial isolates exhibited significant inhibition of efflux activity upon quercetin treatment. Molecular docking studies revealed stability of quercetin-carbapenemase complexes. (i) Virtual superimposition of quercetin onto meropenem, (ii) proximity of quercetin to attacking nucleophile and (iii) involvement of same amino acids that stabilize both meropenem and quercetin - indicated competition between quercetin and meropenem for ligand binding. Although quercetin and PA beta N, a standard efflux pump inhibitor, docked at both central cavity and periplasmic drug binding sites of AcrB, they did not virtually superimpose on each other. However, sufficient release of Gibb's free energy and involvement of same set of amino acids in PA beta N and quercetin stability predicted quercetin's efflux pump inhibitory potential. Hence, quercetin could be potential adjuvant therapeutics for CRGNB-mediated infections.