Ude, Ziga and Flothkötter, Nils and Sheehan, Gerard and Brennan, Marian and Kavanagh, Kevin and Marmion, Celine J. (2021) Multi-targeted metallo-ciprofloxacin derivatives rationally designed and developed to overcome antimicrobial resistance. International Journal of Antimicrobial Agents, 58 (6). p. 106449. ISSN 0924-8579

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Abstract

Antimicrobial resistance is a major global threat to human health due to the rise, spread and persistence of multi-drug-resistant bacteria or ‘superbugs’. There is an urgent need to develop novel chemotherapeutics to overcome this overarching challenge. The authors derivatized a clinically used fluoroquinolone antibiotic ciprofloxacin (Cip), and complexed it to a copper phenanthrene framework. This resulted in the development of two novel metallo-antibiotics of general formula [Cu(N,N)(CipHA)]NO3 where N,N repre�sents a phenanthrene ligand and CipHA represents a hydroxamic acid of Cip derivative. Comprehensive studies, including a detailed proteomic study in which Staphylococcus aureus cells were exposed to the complexes, were undertaken to gain an insight into their mode of action. These new complexes possess potent antibacterial activity against S. aureus and methicillin-resistant S. aureus. In addition, they were found to be well tolerated in vivo in Galleria mellonella larvae, which has both functional and structural similarities to the innate immune system of mammals. These findings suggest that proteins involved in virulence, pathogenesis, and the synthesis of nucleotides and DNA repair mechanisms are most affected. In addition, both complexes affected similar cell pathways when compared with clinically used Cip, including cationic antimicrobial peptide resistance. The Cu-DPPZ-CipHA (DPPZ = dipyrido[3,2-a:2’,3’- c]phenazine) analogue also induces cell leakage, which leads to an altered proteome indicative of reduced virulence and increased stress.

Item Type:	Article
Additional Information:	Cite as: Ziga Ude, Nils Flothkötter, Gerard Sheehan, Marian Brennan, Kevin Kavanagh, Celine J. Marmion, Multi-targeted metallo-ciprofloxacin derivatives rationally designed and developed to overcome antimicrobial resistance, International Journal of Antimicrobial Agents, Volume 58, Issue 6, 2021, 106449, ISSN 0924-8579, https://doi.org/10.1016/j.ijantimicag.2021.106449.
Keywords:	Ciprofloxacin; Metallo-antibiotic; Copper; Hydroxamic acid; Staphylococcus aureus; Proteomic analysis
Academic Unit:	Faculty of Science and Engineering > Biology Faculty of Science and Engineering > Research Institutes > Human Health Institute
Item ID:	17324
Identification Number:	https://doi.org/10.1016/j.ijantimicag.2021.106449
Depositing User:	Dr. Kevin Kavanagh
Date Deposited:	15 Jun 2023 10:22
Journal or Publication Title:	International Journal of Antimicrobial Agents
Publisher:	Elsevier
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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