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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 L 11 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 L 11 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., (© 2024 Wiley‐VCH GmbH.)

The increase in the prevalence of multi‐drug‐resistant bacteria poses a significant healthcare challenge. The urgent need to combat the resistant microbes necessitates discovering new antibacterial agents capable of circumventing the existing resistance mechanisms. Targeting DNA gyrase by suitably modifying the fluoroquinolones can lead to antibiotics with better activity and lower incidence of resistance. The substituted diphenyl ethers like triclosan are known to have potent antibacterial activity. In the current study, the hybridisation of diphenyl ether moiety with fluoroquinolones led to the design and synthesis of new compounds with potent inhibitory activity against staphylococcus aureus with MIC 0.5–64 μg/mL and moderately active against mycobacteria with MIC 2–64 μg/mL. The compounds are non‐toxic to Vero cells with a selectivity index >10 to 200. The compounds also inhibited the resistant strains of S. aureus with a MIC ranging from 0.5–64 μg/mL. The synthesised compounds also exhibited potent anti‐biofilm activity against S. aureus. Furthermore, the DNA supercoiling assay revealed the compounds 7 i, 7 o, 7 p and 7 q showed concentration‐dependant DNA‐Gyrase inhibition at 1 μg/mL. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance is a serious public health risk. Its severity is fueled on an unprecedented scale, necessitating the demand for novel antimicrobial scaffolds aimed at novel targets. Herein, we present cationic chlorpromazine peptide conjugates that are rationally intended to targetmultidrug‐resistant (MDR) bacteria. The most potent compound, CPWL, of all the conjugates evaluated, showed promising antibacterial activity against clinical, MDR S. aureus, with no cytotoxicity. The molecular docking experiments confirmed that CPWL possessed a very high affinity for S. aureus enoyl reductase (saFabI). Furthermore, CPWL antibacterial action against saFabI was further corroborated by MD simulation studies. Thus, our findings highlight cationic chlorpromazine as a promising scaffold for the development of saFabI inhibitors to target severe staphylococcal infections. [ABSTRACT FROM AUTHOR]

Fused‐azepinones are interesting heterocyclic scaffolds present in various natural products and synthetic derivatives with potent kinase inhibition, anti‐cancer, anti‐inflammatory, anti‐HIV, neuroprotective, anti‐fouling and other biological activities. These fused‐azepinones are also known for their antimicrobial activity against the Plasmodium falciparum, Leishmania, Escherichia coli, and Streptococcus pneumonia. In the present work, we synthesized a library of 3,4‐dihydro‐1H‐benzo[b]azepine‐2,5‐dione derivatives and evaluated them for their antibacterial potential against a panel of bacterial pathogens. The Structure‐activity relationship studies revealed the essential structural features for the promising antibacterial properties against Staphylococcus aureus and Mycobacterium tuberculosis with MIC 4–64 μg/mL. In addition, these compounds exhibited favourable selectivity index (SI≥10) in cytotoxicity studies. With the interesting antibacterial properties exhibited and good selectivity index, these compounds have emerged as promising candidates for further development. [ABSTRACT FROM AUTHOR]