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

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-phenant...

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Published in:	Journal of biological inorganic chemistry Vol. 27; no. 1; pp. 201 - 213
Main Authors:	Galdino, Anna Clara Milesi, Viganor, Lívia, Pereira, Matheus Mendonça, Devereux, Michael, McCann, Malachy, Branquinha, Marta Helena, Molphy, Zara, O’Carroll, Sinéad, Bain, Conor, Menounou, Georgia, Kellett, Andrew, dos Santos, André Luis Souza
Format:	Journal Article
Language:	English
Published:	Cham Springer International Publishing 01-02-2022 Springer Nature B.V
Subjects:	Affinity Antimicrobial activity Antimicrobial agents Biochemistry Biomedical and Life Sciences Coordination Complexes - chemistry Coordination Complexes - pharmacology Copper Copper - chemistry Copper - pharmacology Deoxyribonucleic acid DNA DNA - chemistry DNA damage DNA fragmentation DNA topoisomerase Electrostatic properties Ethidium bromide Flow cytometry Hydrogen bonding Hydrophobicity Life Sciences Microbiology Molecular Docking Simulation Multidrug resistance Original Paper Phenanthrolines - chemistry Phenanthrolines - pharmacology Propidium iodide Pseudomonas aeruginosa Silver Silver - pharmacology Toxicity Antimicrobial action DNA oxidative damage Coordination compounds Mechanism of action DNA binding Pseudomonas aeruginosa
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Summary:	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 . Graphical abstract
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0949-8257 1432-1327
DOI:	10.1007/s00775-021-01922-3