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In vivo active organometallic-containing antimycotic agents
Riccardo Rubbiani1, Tobias Weil2, Noemi Tocci2
1Department of Chemistry, University of Zurich Winterthurerstrasse 190 8057 Zurich Switzerland rubbianiric@gmail.com.
Abstract:
Fungal infections represent a global problem, notably for immunocompromised patients in hospital, COVID-19 patient wards and care home settings, and the ever-increasing emergence of multidrug resistant fungal strains is a sword of Damocles hanging over many healthcare systems. Azoles represent the mainstay of antifungal drugs, and their mode of action involves the binding mode of these molecules to the fungal lanosterol 14α-demethylase target enzyme. In this study, we have prepared and characterized four novel organometallic derivatives of the frontline antifungal drug fluconazole (1a-4a). Very importantly, enzyme inhibition and chemogenomic profiling demonstrated that lanosterol 14α-demethylase, as for fluconazole, was the main target of the most active compound of the series, (N-(ferrocenylmethyl)-2-(2,4-difluorophenyl)-2-hydroxy-N-methyl-3-(1H-1,2,4-triazol-1-yl)propan-1-aminium chloride, 2a). Transmission electron microscopy (TEM) studies suggested that 2a induced a loss in cell wall integrity as well as intracellular features ascribable to late apoptosis or necrosis. The impressive activity of 2a was further confirmed on clinical isolates, where antimycotic potency up to 400 times higher than fluconazole was observed. Also, 2a showed activity towards azole-resistant strains. This finding is very interesting since the primary target of 2a is the same as that of fluconazole, emphasizing the role played by the organometallic moiety. In vivo experiments in a mice model of Candida infections revealed that 2a reduced the fungal growth and dissemination but also ameliorated immunopathology, a finding suggesting that 2a is active in vivo with added activity on the host innate immune response.
Insights
Novel organometallic compounds combat drug-resistant fungal infections. A new derivative, 2a, shows potent antifungal activity, even against resistant strains, by targeting the same enzyme as fluconazole.
Area of Science:
- Medicinal Chemistry
- Mycology
- Infectious Diseases
Background:
- Fungal infections pose a significant global health threat, exacerbated by multidrug-resistant strains.
- Azole antifungals, like fluconazole, are crucial but face challenges with emerging resistance.
- Understanding drug-target interactions is key to developing new antifungal therapies.
Purpose of the Study:
- To synthesize and characterize novel organometallic derivatives of fluconazole.
- To evaluate the antifungal activity and mechanism of action of these new compounds.
- To assess the efficacy of the most promising derivative against resistant fungal strains and in vivo models.
Main Methods:
- Synthesis and characterization of four novel organometallic fluconazole derivatives.
- Enzyme inhibition assays and chemogenomic profiling to identify drug targets.
- Transmission electron microscopy (TEM) for cellular analysis.
- Antimicrobial susceptibility testing on clinical isolates and azole-resistant strains.
- In vivo efficacy studies in a murine model of Candida infection.
Main Results:
- Compound 2a, a ferrocenyl derivative, demonstrated significant antifungal activity by inhibiting lanosterol 14α-demethylase.
- 2a induced cell wall damage and signs of apoptosis/necrosis in fungal cells.
- Potency of 2a was up to 400 times higher than fluconazole against certain isolates, including azole-resistant strains.
- In vivo, 2a reduced fungal burden, dissemination, and ameliorated immunopathology in a mouse model.
Conclusions:
- Organometallic modification of fluconazole yields potent antifungal agents, with compound 2a showing exceptional activity.
- The enhanced efficacy, particularly against resistant strains, highlights the crucial role of the organometallic moiety.
- Compound 2a represents a promising therapeutic candidate for invasive fungal infections, with potential immunomodulatory effects.
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