Synergistic Potential of Bis-Benzidinedioxime Palladium(II) and Benzidinedioxime as Enhancers of Gentamicin Efficacy Against Resistant Bacteria: Insights from Molecular Docking and Antimicrobial Studies

The rising threat of antibiotic resistance necessitates innovative strategies to enhance the effectiveness of traditional antibiotics, such as aminoglycosides. This research explores the potential of bis-benzidinedioxime palladium(II) (Pd) and benzidinedioxime (L) as adjuvants to boost Gentamicin (G) activity against resistant strains of Staphylococcus aureus and Salmonella. typhi. Molecular docking using MOE2024 showed that Pd has stronger binding affinities (docking scores: -10.54 to -7.48 kcal/mol) across all aminoglycoside-modifying enzyme targets (1V0C, 3HAM, and 1KNY), especially with 1V0C, which exhibits the strongest interactions due to electrostatic contacts with aspartate and glutamate residues. Benzidinedioxime and Gentamicin had moderate affinities (-7.06 to -6.41 kcal/mol and − 8.33 to -7.6 kcal/mol, respectively). Antimicrobial tests using the cup plate method showed that Pd and L alone had no significant activity (inhibition zones of 0–14 mm), while Gentamicin was ineffective against both strains. However, combinations of G + L and G + Pd showed strong synergy, with inhibition zones of 23–30 mm and 18–24 mm, respectively, especially against S. typhimurium. These findings suggest that benzidinedioxime and bis-benzidinedioxime palladium(II) enhance gentamicin’s effectiveness by strongly inhibiting Aminoglycoside-N-Acetyltransferase-(6')-Ib [AAC(6')-Ib] (PDB: 1V0C) and Aminoglycoside-O-Phosphotransferase-(2'')-IIa [APH(2'')-IIa] (PDB ID: 3HAM). Additionally, bis-benzidinedioxime palladium(II) blocks Aminoglycoside-O-Phosphotransferase-(2'')-IIa [APH(2'')-IIa] without changing the structure of the palladium complex. These results highlight the potential of dinuclear palladium complexes and their ligands as adjuvants to fight against aminoglycoside resistance, laying the groundwork for further studies and the development of new therapies.