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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Veröffentlicht in:Journal of biological inorganic chemistry 2022-02, Vol.27 (1), p.201-213
Hauptverfasser: 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
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container_issue 1
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container_title Journal of biological inorganic chemistry
container_volume 27
creator 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
description 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
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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 . 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The Author(s).</rights><rights>The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). 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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 . 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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</abstract><cop>Cham</cop><pub>Springer International Publishing</pub><pmid>35006347</pmid><doi>10.1007/s00775-021-01922-3</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record>
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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
title 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
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