In Silico Screening of New Delhi metallo- β – lactamase-1(NDM-1) Inhibitors with Drug Reporposing Strategy

Background/Aim: Excessive and improper use of antibiotics in both agricultural and clinical areas has resulted in a rise in bacterial strains that are resistant to several drugs. Among these strains, gram-negative bacteria that produce β-lactamase have become the most common. Given the signifi- cant role of metallo-β-lactamases in biomedicine, it has become imperative to identify inhibitors for these enzymes. NDM1 has exhibited the most rapid and extensive global dissemination among all metallo-β-lactamases, leading to the rapid emergence of bacterial infections containing plasmid-en- coded NDM1 worldwide. Therefore, the goal of this study is to

discover novel and potent inhibitors of NDM1 by employing virtual screening techniques on existing drugs.

Materials and Method: For screening, the 4EXS crystal structure was selected based on information from the literature. All compounds (10767) in the Drugbank database were downloaded and prepared using the LigPrep module. The docking analyses were conducted with Glide’s HTVS/SP/XP docking modules to identify compounds with the highest protein binding, and their effects on the E. coli strain containing the NDM-1 plasmid were assessed and the minimum inhibitory concentrations (MIC’s) determined. Also, the synergistic effects of the drugs were examined with the checkerboard method.

Results: In the virtual screening, it was determined that NADH, Pemetrexed, and Zoledronic acid were hit drugs. The effects of the drugs were examined on the resistant E.coli

strain, and Zoledronic acid was found to be the most effective. MIC values were determined as Ampicillin512, Meropenem16, Imipenem256, Cefotaxime64, NADH>1024, Zoledronic Acid128, and Pemetrexed>1024. Zoledronic acid was found to have additive effects with Ampicillin, synergistic effects with Meropenem, indifference effects with Imipenem, and additive effects with Cefotaxime with the checkerboard method.

Conclusion: This study has shown that Zoledronic acid and Meropenem can be used in combination against
E.coli strains containing NDM-1 plasmid and that they may be potential therapeutic agents.

Atatürk University BAP unit (ProjectID:FBA-2020-8419) financed this research. Keywords: NDM-1, Virtual Screening, Drug Reporposing, Ecoli, In Vitro