Phytochemical screening as an inhibitor of β-lactamases to overcome the carbapenem-resistant of Klebsiella pneumoniae

Abstract

The global emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP) poses a major health challenge due to its resistance to carbapenem antibiotics, such as imipenem and meropenem, primarily mediated by β-lactamases, including NDM and KPC carbapenemases. This study aimed to identify phytochemicals predicted to interact with NDM-1 and KPC-2 β-lactamases, and to determine whether the most promising candidate could enhance carbapenem activity against CRKP. A library of phytochemicals selected for their reported potential to inhibit resistance enzymes rather than for direct antimicrobial activity was screened through ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) profiling, followed by molecular docking against β-lactamase enzymes. Quercetin, eriodictyol, and luteolin showed favorable docking scores of − 9.1, − 8.32, and − 8.66 kcal/mol against KPC-2 and − 8.74, − 8.72, and − 8.73 kcal/mol against NDM-1, respectively. Molecular dynamics simulations were performed to evaluate the conformational behavior of the quercetin–NDM-1 and quercetin–KPC-2 complexes. In vitro assays showed that quercetin, at 2 µg/µL, enhanced the antibacterial activity of carbapenems against a CRKP isolate carrying both bla NDM-1 and bla KPC-2. However, these assays did not directly assess β-lactamase inhibition. These findings support the preliminary potential of quercetin as a carbapenem adjuvant, while the mechanism underlying the observed potentiation requires biochemical confirmation.