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

• DOI: 10.1002/adhm.202400378
• Publication Date: 2024-04-15T22:23:05Z
• Authors: Kajal Chaudhary; Bhumika Agrahari; Bhumika Biswas; Niranjan Chatterjee; Ayushi Chaudhary; Ashwini Kumar; Himanshu Sonker; Sayari Dewan; Deepanshi Saxena; Abdul Akhir; Nidhi Malhotra; Sidharth Chopra; Santosh Misra; Saravanan Mathesw...; Ritika Gautam Singh
• Keywords: 0301 basic medicine; Staphylococcus aureus; Pyridines; Microbial Sensitivity Tests; Staphylococcal Infections; Ligands; Anti-Bacterial Agents; Rats; Rats, Sprague-Dawley; Zinc; 03 medical and health sciences; Coordination Complexes; Biofilms; Animals; Copper

AbstractIn 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.