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

Abstract

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]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 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 (Kapp = 2.55 × 106 M−1) than Ag-phendione (Kapp = 2.79 × 105 M−1) and phendione (Kapp = 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 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. Graphical abstract

The Anti-Leishmania amazonensis and Anti-Leishmania chagasi Action of Copper(II) and Silver(I) 1,10-Phenanthroline-5,6-dione Coordination Compounds

“…AgNPs also induced DNA fragmentation in L. donovani promastigotes, as verified by the TUNEL technique; however, gel electrophoresis showed that DNA breakage was not extensive, indicating the presence of high-molecular-weight DNA fragments of 700 bp [ 44 ]. Interestingly, the treatment of P. aeruginosa with bactericidal concentrations of Cu-phendione induced DNA fragmentation [ 46 ]. Ag-phendione and Cu-phendione were able to bind to double-stranded DNA via hydrogen bonding, hydrophobic and electrostatic interactions.…”

“…Ag-phendione and Cu-phendione were able to bind to double-stranded DNA via hydrogen bonding, hydrophobic and electrostatic interactions. In addition, Cu-phendione was able to induce topoisomerase I mediated DNA relaxation of supercoiled plasmid DNA, in addition to inducing oxidative DNA injuries [ 46 ].…”

Antibacterial activity of metal–phenanthroline complexes against multidrug-resistant Irish clinical isolates: a whole genome sequencing approach

“…3 ). Ag(I) complexed to phen or a phen-type ligand (e.g., phendione) have presented with additional routes in which they exert their toxicity against microorganisms, such as interacting with double stranded DNA [ 36 ] or suppressing virulence [ 35 ]. Cu(II) and Mn(II)-phen complexes have been reported to be avid producers of ROS [ 112 ] which is thought to cause cell membrane damage and thiol depletion.…”

“…They were effective inhibitors of the metalloenzyme Elastase B (lasB), which is secreted by P. aeruginosa , suggesting this as a novel potential chemotherapeutic target [ 35 ]. Moreover, they were able to interact with double-stranded DNA and promote oxidative damage, suggesting multiple mechanisms of action in P. aeruginosa [ 36 ].…”

In Vitro Effects of Aminopyridyl Ligands Complexed to Copper(II) on the Physiology and Interaction Process of Trypanosoma cruzi

“…In this scenario, the use of metal complexes associated with repurposed/novel drugs is a new line of research that is gaining attention, since many of these compounds can be bactericidal, fungicidal, and even present antiparasitic action [ 13 , 14 , 15 , 16 , 17 , 18 ]. In this sense, a previous study from our group showed that two aminopyridine derivatives complexed with Cu 2+ , namely, cis -aquadichloro( N -[4-(hydroxyphenyl)methyl]-2-pyridinemethamino)copper ( 3a ) and its glycosylated ligand cis -dichloro( N -{[4-(2,3,4,6-tetra- O -acetyl-β-D-glucopyranosyloxy)pheny]lmethyl}-2-pyridinemethamino)copper ( 3b ), were effective against the infective form (trypomastigote) of T. cruzi , while non-toxic action was reported for RAW macrophages [ 19 ].…”