4.7 Article

Multi-targeted metallo-ciprofloxacin derivatives rationally designed and developed to overcome antimicrobial resistance

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Publisher

ELSEVIER
DOI: 10.1016/j.ijantimicag.2021.106449

Keywords

Ciprofloxacin; Metallo-antibiotic; Copper; Hydroxamic acid; Staphylococcus aureus; Proteomic analysis

Funding

  1. Science Foundation Ireland [11/RFP.1/CHS/3095, 17/TIDA/5009]
  2. Maynooth University Doctoral Hume Scholarship
  3. Science Foundation Ireland (SFI)
  4. European Regional Development Fund [12/RC/2275_P2]
  5. SFI Research Infrastructure Call 2012 [12/RI/2346 (3)]
  6. Science Foundation Ireland (SFI) [17/TIDA/5009] Funding Source: Science Foundation Ireland (SFI)

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Researchers have developed two novel metallo-antibiotics that show potent antibacterial activity against Staphylococcus aureus and methicillin-resistant S. aureus, while also exhibiting good tolerability in larvae. These complexes affect various proteins involved in bacterial virulence, pathogenesis, and DNA repair mechanisms.
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 represents 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. (C) 2021 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.

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