In Silico Design of Benzimidazole Derivatives as Dual Inhibitors of AcrB Efflux Pump and NDM-1 to Combat Antibiotic Resistance

Antibiotic resistance poses a critical global health threat, necessitating new strategies to address multidrug-resistant bacteria. This study presents the in silico design and evaluation of five novel benzimidazole derivatives (B1–B5) as dual-action inhibitors targeting both the AcrB efflux pump and NDM-1 carbapenemase two major contributors to antibiotic resistance in Gram-negative pathogens. Computational tools, including Chemdraw, Spartan14, Chimera, Autodock Vina, and Biovia Discovery Studio, were employed for molecular modeling, docking, and visualization of key molecular interactions. All compounds satisfied Lipinski’s rule of five, exhibited high predicted gastrointestinal absorption, and demonstrated favorable pharmacokinetic profiles. Toxicity assessments indicated low to moderate risk, with B4 identified as the safest candidate (LD50: 3420 mg/kg). Molecular docking revealed that B1 and B5 displayed superior binding affinities to NDM-1 (-6.9 and -7.0 kcal/mol, respectively), outperforming the native ligand, while B3 and B4 matched or exceeded the native ligand’s binding to AcrB (-11.1 and -11.0 kcal/mol). Detailed interaction analysis highlighted the importance of hydrogen bonds, pi-alkyl, and pi-pi stacking in stabilizing these complexes. These findings suggest that the designed benzimidazole derivatives hold promise as dual-target inhibitors, offering a potential pathway for developing new therapeutics to combat antibiotic resistance. Further experimental validation is recommended to confirm these computational results and advance these candidates toward clinical application.