Related Experiment Video
Updated: May 15, 2025
Whole Genome Sequencing of Candida glabrata for Detection of Markers of Antifungal Drug Resistance
Published on: December 28, 2017
Synergistic Antifungal Activity of Pentamidine and Auranofin Against Multidrug-Resistant Candida auris
Yasmim Isabel Retore1, Fabíola Lucini1, Simone Simionatto1
1Health Sciences Research Laboratory, Universidade Federal of Grande Dourados, Rodovia Dourados - Itahum km 12, Cidade Universitária, Dourados, Mato Grosso do Sul, CEP: 79804970, Brazil.
Background:
Candida auris is a significant clinical concern due to its ability to cause outbreaks in healthcare settings and its common resistance to current treatments. This highlights the need for alternative therapies. Drug repurposing offers a promising approach, and the combination of pentamidine (antiprotozoal) and auranofin (anti-rheumatic) has shown potential antifungal activity against Candida species, including C. auris. This study aimed to evaluate the antifungal activity of pentamidine and auranofin, both individually and in combination, against C. auris.
Methods:
Minimum Inhibitory Concentrations (MICs) were determined following CLSI guidelines, and drug interactions were assessed using the checkerboard microdilution method. Additional evaluations included growth inhibition, antibiofilm activity, cell damage, sorbitol protection, and efflux pump inhibition. Nucleotide leakage and cell membrane permeability were analyzed using biochemical assays. In vivo efficacy was tested using a Tenebrio molitor larvae model infected with C. auris.
Results:
The MICs of pentamidine against C. auris ranged from 16 to 128 microg/mL, showing fungicidal activity. The combination with auranofin had a synergistic effect (FICI: 0.37) and exhibited a fungistatic effect in growth inhibition assays. Auranofin was most effective at inhibiting biofilm formation. Pentamidine impaired mitochondrial function, leading to cellular respiration issues and membrane damage. Efflux pump assays indicated activation by both drugs, potentially influencing resistance. In vivo tests showed both drugs significantly improved survival rates in infected larvae compared to fluconazole.
Conclusion:
In conclusion, pentamidine and auranofin, either individually or in combination, are promising treatments for C. auris and warrant further research into optimal dosing and combination strategies.
Insights
Pentamidine and auranofin show promise as new treatments for Candida auris infections. Their combination demonstrated synergistic antifungal activity and improved survival in vivo, suggesting potential for drug repurposing.
Area of Science:
- Antimicrobial drug discovery
- Fungal infectious diseases
- Drug repurposing
Background:
- Candida auris poses a significant threat due to multidrug resistance and healthcare-associated outbreaks.
- Alternative therapeutic strategies are urgently needed to combat C. auris infections.
- Drug repurposing, specifically combining pentamidine and auranofin, presents a potential avenue for novel antifungal treatments.
Purpose of the Study:
- To evaluate the individual and combined antifungal activity of pentamidine and auranofin against Candida auris.
- To investigate the mechanisms underlying the antifungal effects of these drugs.
- To assess the in vivo efficacy of pentamidine and auranofin in a relevant model.
Main Methods:
- Minimum Inhibitory Concentrations (MICs) and drug synergy (FICI) determined via checkerboard microdilution.
- Assays for growth inhibition, antibiofilm activity, cell damage, and efflux pump inhibition.
- Biochemical analysis of nucleotide leakage and membrane permeability; in vivo efficacy in Tenebrio molitor larvae.
Main Results:
- Pentamidine exhibited fungicidal activity (MICs 16-128 µg/mL).
- The pentamidine-auranofin combination showed synergy (FICI: 0.37) and fungistatic effects.
- Pentamidine disrupted mitochondrial function; both drugs activated efflux pumps. Auranofin inhibited biofilm formation.
- Both drugs significantly enhanced larval survival compared to fluconazole.
Conclusions:
- Pentamidine and auranofin demonstrate significant potential as standalone or combination therapies against C. auris.
- Further research is warranted to optimize dosing and combination strategies for clinical application.
- These repurposed drugs offer a promising alternative to existing treatments for challenging C. auris infections.
