Pyridine‐2,6‐Dicarboxamide Proligands and their Cu(II)/Zn(II) Complexes Targeting Staphylococcus Aureus for the Attenuation of In Vivo Dental Biofilm

Abstract In the pursuit to combat stubborn bacterial infections, particularly those stemming from gram‐positive bacteria, this study is an attempt to craft a precision‐driven platform characterized by unparalleled selectivity, specificity, and synergistic antimicrobial mechanisms. Leveraging remarkable potential of metalloantibiotics in antimicrobial applications, herein, this work rationally designs, synthesizes, and characterizes a new library of Pyridine‐2,6‐dicarboxamide ligands and their corresponding transition metal Cu(II)/Zn(II) complexes. The lead compound L¹¹ demonstrates robust antibacterial properties against Staphylococcus aureus (Minimum Inhibitory Concentration (MIC) = 2–16 µg mL⁻¹), methicillin and vancomycin‐resistant S. aureus (MIC = 2–4 µg mL⁻¹) and exhibit superior antibacterial activity when compared to FDA‐approved vancomycin, the drug of last resort. Additionally, the compound exhibits notable antimicrobial efficacy against resistant enterococcus strains (MIC = 2–8 µg mL⁻¹). To unravel mechanistic profile, advanced imaging techniques including SEM and AFM are harnessed, collectively suggesting a mechanistic pathway involving cell wall disruption. Live/dead fluorescence studies further confirm efficacy of L¹¹ and its complexes against S. aureus membranes. This translational exploration extends to a rat model, indicating promising in vivo therapeutic potential. Thus, this comprehensive research initiative has capabilities to transcends the confines of this laboratory, heralding a pivotal step toward combatting antibiotic‐resistant pathogens and advancing the frontiers of metalloantibiotics‐based therapy with a profound clinical implication.