The Antifungal Potential of Niclosamide and Structurally Related Salicylanilides
Abstract
:1. Introduction
2. Methodology
3. Niclosamide: Chemistry, Pharmacology, and Antifungal Activity
3.1. Chemistry
3.2. Pharmacology
3.3. Antifungal Activity
3.3.1. Activity against Pathogenic Ascomycetes
3.3.2. Activity against Pathogenic Basidiomycetes
Phylum | Fungus | Activity/Mechanism | Reference |
---|---|---|---|
Ascomycetes | Candida albicans (including azole-resistant strains) | Inhibition of filamentation, biofilm formation, and invasion of host cells (no growth inhibition); retrograde response; possible targets Mge1 and mitochondrial protein import complex | [51] |
Candida albicans (including azole-resistant strains), Candida auris | Blocking of biofilm formation via NDU1 inhibition, increased ROS formation, suppressed mitochondrial oxygen consumption, and protection of mice from infection | [52] | |
Trichophyton tonsurans | Strong growth inhibition (MIC < 1 µM) | [57] | |
Sporothrix brasiliensis | Broad-spectrum growth inhibition (MIC = 0.625–2.5 µM, wildtype and non-wildtype strains); fungicidal | [60,61] | |
Paracoccidioides brasiliensis | Fungicidal (1 µM) | [60] | |
Histoplasma capsulatum | Fungicidal (1 µM) | [60] | |
Madurella mycetomatis | Growth inhibition of SO1 and CBS131320 isolates (MIC = 0.79–1.6 µg/mL) | [66] | |
Basidiomycetes | Cryptococcus neoformans | Growth inhibition of H99 wildtype strain (IC50 = 0.17 µM) and nine clinical isolates (IC50 = 0.17–0.52 µM) under nutrient-starvation conditions | [71] |
Cryptococcus neoformans | Growth inhibitory and fungicidal effects on the JEC21 isolate (MIC < 0.78 µg/mL, MFC = 1.56 µg/mL); inhibition of spore germination | [72] |
4. Antifungal Activity of Other Salicylanilides
4.1. Oxyclozanide
4.2. Further Salicylanilide Drugs with Antifungal Activity
4.2.1. 3,5-Diiodosalicylanilides
Compound | Fungus | Activity/Mechanism | Reference |
---|---|---|---|
Oxyclozanide | Candida albicans | Inhibition of growth and filamentation | [51] |
Candida albicans | Active in glucose-free medium with non-fermentable carbon sources (ethanol, glycerol); disruption of mitochondrial membrane potential | [77] | |
Madurella mycetomatis | Low activity | [76] | |
Closantel | Trichophyton tonsurans | Active (MIC < 1 µM) | [57] |
Rafoxanide | Aspergillus fumigatus (resistant strains with upregulated Cyp51A) | Active (MIC = 2–8 µg/mL); suppression of Cyp51A; sensitization to fluconazole; in vivo activity (sub-MIC doses) in albino mice in combination with fluconazole (survival rate 60%) | [88] |
Candida albicans (resistant strains with upregulated Erg11) | Active (MIC = 2–8 µg/mL); suppression of Erg11; sensitization to fluconazole; in vivo activity (sub-MIC doses) in albino mice in combination with fluconazole (survival rate 70%) | [88] | |
Bromsalans | Aspergillus niger, Candida albicans, Pityrosporum ovale | Growth inhibition; dibromsalan more active than tribromsalan against C. albicans and P. ovale; Miranol CS formulation enhanced antifungal activity | [16] |
Tribromsalan | C. albicans | Growth inhibition (20 µM); low inhibition of C. albicans filamentation | [51] |
4.2.2. Bromsalans
4.3. Experimental Salicylanilide Compounds
Compound | Fungus | Activity/Mechanism | Reference |
---|---|---|---|
Salicylanilide | Candida albicans | Inhibition of growth and filamentation | [51] |
TCSA | Candida albicans (including azole-resistant strains) | Inhibition of filamentation; no growth inhibition | [51] |
MMV665907 | Madurella mycetomatis | Active (MIC = 1.6 µg/mL, SO1 and CBS131320) | [66] |
(S)-4-Bromo-2-(4-(trifluoromethyl)phenylcarbamoyl)phenyl 2-acetamido-3-phenylpropanoate | Trichophyton mentagrophytes | Active (MIC = 3.9–7.8 µM) | [94] |
5-Chloro-2-(3,4-dichlorophenylcarbamoyl)phenyl benzoate | Trichosporon asahii | Active (MIC = 3.9 µM); medium acidification (pH 5); reduced activity | [95] |
Candida krusei Trichophyton mentagrophytes | Moderate activity (MIC = 15.6 µM, C. krusei; MIC = 31.3 µM, T. mentagrophytes) | [95] | |
2-(4-Bromophenylcarbamoyl)-5-chlorophenyl-4-(trifluoromethyl)benzoate 5-Chloro-2-(4-(trifluoromethyl)phenylcarbamoyl)phenyl-4-(trifluoromethyl)benzoate | Trichophyton mentagrophytes | Active (MIC = 0.49 µM) | [96] |
4.4. Structure–Activity Relationships
5. Discussion of Current Challenges and Opportunities
5.1. Antifungal Activity and Mechanisms
5.2. Salicylanilide Resistance and Possible Combination Partners
5.3. Adverse Effects, Drug–Drug Interactions, and Drug Availability
6. Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Biersack, B. The Antifungal Potential of Niclosamide and Structurally Related Salicylanilides. Int. J. Mol. Sci. 2024, 25, 5977. https://doi.org/10.3390/ijms25115977
Biersack B. The Antifungal Potential of Niclosamide and Structurally Related Salicylanilides. International Journal of Molecular Sciences. 2024; 25(11):5977. https://doi.org/10.3390/ijms25115977
Chicago/Turabian StyleBiersack, Bernhard. 2024. "The Antifungal Potential of Niclosamide and Structurally Related Salicylanilides" International Journal of Molecular Sciences 25, no. 11: 5977. https://doi.org/10.3390/ijms25115977