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Nature ETN and Dr Andrew Kellett’s group
June 16, 2022

The Nature-ETN (Nucleic acids for future gene editing, immunotherapy and epigenetic sequence modification) is coordinated by SSPC funded investigator Dr Andrew Kellett, Dublin City University, (DCU) Ireland. The purpose of Nature-ETN is to leverage recent breakthrough discoveries in epigenetic manipulation, gene editing, small molecule DNA targeting, and rapid gene/transgene detection to extend the boundaries of molecular medicine and provide new tools for treating cancer and monogenetic diseases.

A new publication from Nature ETN examines the multi-modal activity of copper (II) and Silver (I)- Phendione complexes on DNA scission within P. Aeruginosa.

Recent collaborative work from NATURE-ETN has been published in the Journal of Biological Inorganic Chemistry by researchers in the Kellett lab at DCU. Co-authors include NATURE-ETN coordinator Dr Andrew Kellett, co-supervisor Dr Georgia Menounou, and ESR Conor Bain. The paper investigated the multi-modal activity of copper(II) and silver(I) complexes with the N,N-coordinating ligand, 1,10-phenanthroline-5,6-dione, with particular focus on DNA damage within Pseudomonas aeruginosa.

The emergence of microbial drug-resistance in recent decades has given rise to the need for novel antimicrobial therapeutics. The metal-based complexes [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) have previously demonstrated efficient antimicrobial action against multidrug-resistant species. The focus of the study was to understand the binding potential of these complexes with double-stranded DNA using a combination of in silico and in vitro approaches. Promising results arising from this work revealed a potentially new class of antimicrobial drug candidate with a distinct therapeutic mechanism against the multidrug-resistant pathogen P. aeruginosa.

Molecular docking studies showed both complexes elicit a multi-mechanistic approach to DNA-binding via hydrogen bonding, hydrophobic and electrostatic interactions, with both complexes favouring minor groove binding. Of the two complexes, Cu-phendione achieved the highest binding affinity for both major and minor grooves with nearly 10x greater affinity to DNA than Ag-phendione and nearly 20x greater affinity than the phendione ligand alone. Cu-phendione achieved DNA scission through free radical oxidative damage, as well as DNA-nicking and relaxation of supercoiled plasmid DNA. It was concluded that both complexes elicit a dose-dependent effect, with successful DNA fragmentation within multi-drug resistant pathogen P. aeruginosa when treated with a single dose of Cu-phendione. This work proposes a novel dose-regulated class of metal-based antimicrobial therapeutics.

Reference:

Galdino, A.C.M., Viganor, L., Pereira, M.M., Devereux, M., McCann, M., Branquinha, M.H., Molphy, Z., O’Carroll, S., Bain, C., Menounou, G., Kellett, A., Dos Santos, A.L.S. 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 aeruginosaJ Biol Inorg Chem (2022): https://doi.org/10.1007/s00775-021-01922-3

The group recently had a training week in collaboration with Nature Publishing Group in LMU Munich: https://www.nature-etn.eu/2022/05/25/third-nature-etn-training-week-in-munich-germany/ and attended the SCNAC meeting (https://www.nature-etn.eu/2022/06/14/a-delegation-of-nature-etn-esrs-at-the-scnac-2022-conference/).

Source: https://www.nature-etn.eu/tag/msca-itn/

Check out two outputs from the Kellett group in Nucleic Acids Research and Angewandte Chemie in collaboration with Tom Brown, Oxford:

Bríonna McGorman, Nicolò Zuin Fantoni, Sinéad O’Carroll, Anna Ziemele, Afaf H El-Sagheer, Tom Brown, Andrew Kellett, Enzymatic Synthesis of Chemical Nuclease Triplex-Forming Oligonucleotides with Gene-Silencing Applications, Nucleic Acids Research, Volume 50, Issue 10, 10 June 2022, Pages 5467–5481, https://doi.org/10.1093/nar/gkac438

Joseph Hennessy, Bríonna McGorman, Dr. Zara Molphy, Prof. Nicholas P. Farrell, Dr. Daniel Singleton, Prof. Tom Brown, Prof. Andrew Kellett, A Click Chemistry Approach to Targeted DNA Crosslinking with cis -Platinum(II)-Modified Triplex-Forming Oligonucleotides, Angewandte Chemie, Volume 61, Issue 3, 17 January 2022, https://doi.org/10.1002/anie.202110455

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