Pyridine-2,6-dicarboxamide proligands and their Cu(II)/Zn(II) complexes Targeting Staphylococcus Aureus for the Attenuation of In-vivo Dental Biofilm.

In the pursuit to combat stubborn bacterial infections, particularly those stemming from gram-positive bacteria, our 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, we rationally design, synthesize, and characterize a new library of Pyridine-2,6-dicarboxamide ligands and their corresponding transition metal Cu(II)/Zn(II) complexes. The lead compound L11 demonstrate robust antibacterial properties against Staphylococcus aureus (MIC = 2-16 µg/mL), methicillin and vancomycin-resistant S. aureus (MIC = 2-4 µg/mL) and exhibit superior antibacterial activity when compared to FDA-approved vancomycin, the drug of last resort. Additionally, the compound exhibited notable antimicrobial efficacy against resistant enterococcus strains (MIC = 2-8 µg/mL). To unravel mechanistic profile, advanced imaging techniques including SEM and AFM were 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. Our translational exploration extends to a rat model, indicating promising In-vivo therapeutic potential. Thus, our comprehensive research initiative has capabilities to transcends the confines of our laboratory, heralding a pivotal step toward combatting antibiotic-resistant pathogens and advancing the frontiers of metalloantibiotics based therapy with a profound clinical implication. This article is protected by copyright. All rights reserved.