Antibiotic Resistance Strategies and In Silico Screening: Genetic Engineering, NDM-1, and Natural Inhibitors

الملخص

   The rise of bacteria that produce New Delhi metallo-β-lactamase-1 (NDM-1) is extremely dangerous for the world, as they show high levels of antibiotic resistance. Developing new strategies aimed at these multi-drug resistant targets is greatly needed, and the use of natural products is especially promising. The goal of this study is the assessment of the inhibitory effect of the three natural products—Baicalin, Myricetin and Rosmarinic Acid—against the NDM-1 enzyme through in silico analyses of molecular docking (with ADME and toxicity profiling) and its subsequent assessment as a reliable tool for predicting enzyme inhibition. Binding affinity, the inhibition constants (Ki) and ligand efficiency of the NDM-1 enzyme (PDB ID: 3QS0) were calculated and assessed using molecular docking simulations. The software InstaDock with the QuickVina-W scoring algorithm was used for these calculations. The ADME processes (Absorption, Distribution, Metabolism, and Excretion) were calculated along with drug-likeness and acute toxicity (LD50) estimations with the platforms SwissADME and ProTox- II. The three compounds evaluated also exhibited acceptable ranges of binding affinity, which were calculated from -5.7 to -7.7 kcal/mol. With a binding affinity of -7.7 kcal/mol, Baicalin is predicted to have a Ki of 0.2406 μM and pKi of 5.65. Myricetin is predicted to have moderate binding and a Ki of 0.2739 μM at -6.3 kcal/mol, and Rosmarinic Acid predicted a binding affinity of -5.7 kcal/mol. Interaction analyses determined that multiple hydrophobic bond and hydrogen bond interactions were present with active site residues such as His122, His189, His250, Asp124, Lys211 and Asn220. According to OECD standards, all compounds exhibited positive ADME results and low toxicity (LD50 >300 mg/kg for all routes), classifying them as safe. This shows that Baicalin, Myricetin, and Rosmarinic Acid are good pharmacokinetics NDM-1 inhibitors and safe. Additional research is necessary to find possible therapies for NDM-1 mediated antibiotic resistance.