PubReading [186] - Copper(II) and silver(I)‐1,10‐phenanthroline‐5,6‐dione complexes interact with double‐stranded DNA: further evidence of their apparent multi‐modal activity towards Pseudomonas aeruginosa - A. Galdino, A. los Santos et al.

<p>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-phenan- throline-5,6-dione)2]ClO4 (Ag-phendione) and [Cu(1,10-phenanthroline-5,6-dione)3](ClO4)2.4H2O (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 dock- ing 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 eth- idium bromide displacement technique revealed Cu-phendione has a higher binding affinity to DNA (<em>K</em>app = 2.55 × 106 M−1) than Ag-phendione (<em>K</em>app = 2.79 × 105 M−1) and phendione (<em>K</em>app = 1.33 × 105 M−1). Cu-phendione induced topoisomerase I-mediated DNA relaxation of supercoiled plasmid DNA. Moreover, Cu-phendione was able to induce oxidative DNA inju- ries with the addition of free radical scavengers inhibiting DNA damage. Ag-phendione and Cu-phendione avidly displaced propidium iodide bound to DNA in permeabilized <em>Pseudomonas aeruginosa </em>cells in a dose-dependent manner as judged by flow cytometry. The treatment of <em>P. aeruginosa </em>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 multi