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New Peptide Based Fluconazole Conjugates with Expanded Molecular Targets
Wioletta Brankiewicz1, Joanna Okońska2, Katarzyna Serbakowska1
1Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdańsk University of Technology, Narutowicza 11/12, 80-233 Gdańsk, Poland.
Pharmaceutics
|April 23, 2022
Summary
New antifungal drug conjugates combining fluconazole (FLC) with peptides show potent activity against fluconazole-resistant Candida albicans. These novel agents target cell membranes with low human cell toxicity, offering promising alternatives for treating dangerous fungal infections.
Area of Science:
- Medicinal Chemistry
- Mycology
- Drug Discovery
Background:
- * *Candida* spp. infections are commonly treated with azole antifungals, with fluconazole (FLC) being the most widely used clinical agent.
- * Combined antifungal therapies show promise for treating severe systemic *Candida* infections.
- * Development of novel antifungal agents is crucial due to rising resistance.
Purpose of the Study:
- * To design, synthesize, and evaluate novel conjugates linking fluconazole (FLC) to cell-penetrating or antimicrobial peptides.
- * To assess the biological activity of these conjugates against *Candida albicans*, including fluconazole-resistant strains.
- * To investigate the mechanism of action and cytotoxicity of the most promising conjugates.
Main Methods:
- * Synthesis of five FLC-peptide conjugates, varying in peptide sequence and linkage site.
- * Antifungal activity testing against reference and clinical isolates of *C. albicans* using standard assays.
- * Mechanism of action studies using fluorescence microscopy, scanning electron microscopy, and flow cytometry.
- * Cytotoxicity assessment against human cells.
Main Results:
- * Two conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10-7-NH2, demonstrated high activity against fluconazole-susceptible and resistant *C. albicans* strains.
- * These conjugates exhibited enhanced fungicidal effects compared to fluconazole alone and targeted the cell membrane.
- * The active conjugates displayed low cytotoxicity towards human cells, with IC90 values comparable to MIC50 values against *C. albicans*.
- * Conjugation via the hydroxyl group of FLC was essential for activity; linkage via the triazole ring nitrogen resulted in inactive compounds.
Conclusions:
- * Novel fluconazole-peptide conjugates, particularly FLCpOH-TP10-NH2 and FLCpOH-TP10-7-NH2, are effective against *C. albicans*, including resistant strains.
- * These conjugates represent potential candidates for new antifungal therapies due to their potent activity, targeted mechanism, and favorable safety profile.
- * The linkage strategy is critical for the antifungal efficacy of FLC-peptide conjugates.
Keywords:
Candidaantimicrobial peptidescell penetrating peptidesfluconazolepeptide-drug conjugatesresistanceMore Related Videos
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