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Fluoroquinolone Metalloantibiotics: A Promising Approach against Methicillin-Resistant Staphylococcus aureus
Mariana Ferreira1, Lucinda J Bessa1, Carla F Sousa1
1REQUIMTE-LAQV (Rede de Química e Tecnologia - Laboratório Associado para a Química Verde), Departamento de Química e Bioquímica da Faculdade de Ciências da Universidade do Porto, Rua do Campo Alegre, s/n, 4169-007 Porto, Portugal.
Abstract:
Fluoroquinolones (FQs) are antibiotics commonly used in clinical practice, although nowadays they are becoming ineffective due to the emergence of several mechanisms of resistance in most bacteria. The complexation of FQs with divalent metal ions and phenanthroline (phen) is a possible approach to circumvent antimicrobial resistance, since it forms very stable complexes known as metalloantibiotics. This work is aimed at determining the antimicrobial activity of metalloantibiotics of Cu(II)FQphen against a panel of multidrug‑resistant (MDR) clinical isolates and to clarify their mechanism of action. Minimum inhibitory concentrations (MICs) were determined against MDR isolates of Escherichiacoli,Pseudomonasaeruginosa and methicillin-resistant Staphylococcus aureus (MRSA). Metalloantibiotics showed improved antimicrobial activity against several clinical isolates, especially MRSA. Synergistic activity was evaluated in combination with ciprofloxacin and ampicillin by the disk diffusion and checkerboard methods. Synergistic and additive effects were shown against MRSA isolates. The mechanism of action was studied though enzymatic assays and atomic force microscopy (AFM) experiments. The results indicate a similar mechanism of action for FQs and metalloantibiotics. In summary, metalloantibiotics seem to be an effective alternative to pure FQs against MRSA. The results obtained in this work open the way to the screening of metalloantibiotics against other Gram‑positive bacteria.
Insights
Metalloantibiotics, complexes of fluoroquinolones (FQs) with metal ions, show enhanced antimicrobial activity against multidrug-resistant bacteria, particularly MRSA. These compounds offer a promising alternative to conventional FQs for combating antimicrobial resistance.
Area of Science:
- Microbiology
- Infectious Diseases
- Medicinal Chemistry
Background:
- Fluoroquinolones (FQs) efficacy is declining due to widespread bacterial resistance.
- Antimicrobial resistance poses a significant global health threat.
- Metalloantibiotics, formed by complexing FQs with metal ions and phenanthroline, are being explored to overcome resistance.
Purpose of the Study:
- To evaluate the antimicrobial activity of copper(II) fluoroquinolone phenanthroline (Cu(II)FQphen) metalloantibiotics against multidrug-resistant (MDR) clinical isolates.
- To elucidate the mechanism of action of these novel metalloantibiotics.
- To assess synergistic effects with existing antibiotics.
Main Methods:
- Minimum Inhibitory Concentration (MIC) determination against MDR Escherichia coli, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus (MRSA).
- Disk diffusion and checkerboard assays to evaluate synergistic activity with ciprofloxacin and ampicillin.
- Enzymatic assays and Atomic Force Microscopy (AFM) to investigate the mechanism of action.
Main Results:
- Metalloantibiotics demonstrated improved antimicrobial activity, especially against MRSA isolates.
- Synergistic and additive effects were observed when metalloantibiotics were combined with ciprofloxacin and ampicillin against MRSA.
- The mechanism of action of metalloantibiotics was found to be similar to that of FQs.
Conclusions:
- Metalloantibiotics represent a viable alternative to traditional fluoroquinolones for treating infections caused by MRSA.
- Further research into metalloantibiotics against other Gram-positive bacteria is warranted.
- This study highlights the potential of metalloantibiotics in the fight against antimicrobial resistance.
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