Search

Tackling microbial resistance requires continuous efforts for the development of new molecules with novel mechanisms of action and potent antimicrobial activity. Our group has previously identified metal-based compounds, [Ag(1,10-phenanthroline-5,6-dione) 2 ]ClO 4 (Ag-phendione) and [Cu(1,10-phenanthroline-5,6-dione) 3 ](ClO 4 ) 2 .4H 2 O (Cu-phendione), with efficient antimicrobial action against multidrug-resistant species. Herein, we investigated the ability of Ag-phendione and Cu-phendione to bind with double-stranded DNA using a combination of in silico and in vitro approaches. Molecular docking revealed that both phendione derivatives can interact with the DNA by hydrogen bonding, hydrophobic and electrostatic interactions. Cu-phendione exhibited the highest binding affinity to either major (- 7.9 kcal/mol) or minor (- 7.2 kcal/mol) DNA grooves. In vitro competitive quenching assays involving duplex DNA with Hoechst 33258 or ethidium bromide demonstrated that Ag-phendione and Cu-phendione preferentially bind DNA in the minor grooves. The competitive ethidium bromide displacement technique revealed Cu-phendione has a higher binding affinity to DNA (K app  = 2.55 × 10 6  M -1 ) than Ag-phendione (K app  = 2.79 × 10 5  M -1 ) and phendione (K app  = 1.33 × 10 5  M -1 ). Cu-phendione induced topoisomerase I-mediated DNA relaxation of supercoiled plasmid DNA. Moreover, Cu-phendione was able to induce oxidative DNA injuries with the addition of free radical scavengers inhibiting DNA damage. Ag-phendione and Cu-phendione avidly displaced propidium iodide bound to DNA in permeabilized Pseudomonas aeruginosa cells in a dose-dependent manner as judged by flow cytometry. The treatment of P. aeruginosa with bactericidal concentrations of Cu-phendione (15 µM) induced DNA fragmentation as visualized by either agarose gel or TUNEL assays. Altogether, these results highlight a possible novel DNA-targeted mechanism by which phendione-containing complexes, in part, elicit toxicity toward the multidrug-resistant pathogen P. aeruginosa., (© 2022. The Author(s).)

Two complexes [AgI(pmtbH)] 4 (1) and {[Ag 4 (pmtbH) 4 (NO 3 ) 4 ·2X} n (2) (where pmtbH is 2-[(2-pyridinylmethyl)thio]-1H-benzimidazole and X is H 2 O or MeOH) were synthesised and structurally characterised. Complex 2 showed therapeutic potential against Candida albicans, Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa but complex 1 did not show significant activity in vitro. Further in vivo studies using larvae of the insect Galleria mellonella indicated that complex 2 significantly stimulates the immune system and that pre-treatment with the complex offers appreciable protection against all three bacteria. Real-time flow cytometry data support the observed antimicrobial profile of complex 2 and suggest the antimicrobial response may be linked to a form of bacterial programmed cell death (PCD). Complex 2 was found to interact with DNA in the bacterial and fungal cells but it did not cleave plasmid DNA isolated from the three bacteria., (Copyright © 2018 Elsevier Inc. All rights reserved.)