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, 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