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.
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 aeruginosa. J 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/).
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