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Identification of efflux inhibitors through a drug repurposing strategy in Candida albicans
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Resumo(s)
Introduction – Candida albicans is a major cause of nosocomial fungal infections, often associated with high morbidity and mortality. The rising resistance to antifungal drugs, particularly azoles, underscores the need for new therapeutic strategies. Among resistance mechanisms, alterations in drug targets and overexpression of efflux pump genes play key roles. Efflux inhibitors can enhance the intracellular drug accumulation, thereby restoring antifungal efficacy and preventing resistance development. Drug repurposing offers a cost-effective and time-efficient alternative for identifying new drugs, including efflux inhibitors. In this study, we used an in silico drug repurposing approach to identify approved drugs associated with membrane transport functions and evaluate their efflux-modulating potential in vitro. Methods – Using the DrugBank database, we screened predicted membrane transport proteins in C. albicans and selected those with homology to known drug targets. A subset of drugs, representative of each chemical group, was selected for in vitro screening against the reference strain C. albicans ATCC 90028. We further evaluated the potential adjuvant effect of these drugs on the activity of fluconazole. Finally, the efflux inhibitory effect of the candidate drugs was assessed by real-time fluorometric detection of ethidium bromide accumulation. Results – A total of 245 predicted membrane transport proteins were screened, 51 of which showed homology to known drug targets and were associated with 777 drugs. A subset of 59 drugs was selected for screening. The drug miltefosine showed the lowest minimum inhibitory concentration (MIC; 2 mg/L), while amlodipine and procainamide demonstrated an adjuvant effect by decreasing the MIC of fluconazole by at least four-fold. Fluorometric assays revealed amlodipine, fluvoxamine and fluoxetine as potential efflux inhibitors in C. albicans. Discussion – These findings highlight the potential of these drugs to contribute to the research and development of new therapeutic alternatives aimed at combating antifungal resistance.
Descrição
Funding information: The author(s) declared that financial support was received for this work and/or its publication. This work is funded by national funds through FCT – Fundação para a Ciência e a Tecnologia, I.P., under the R&D unit Global Health and Tropical Medicine (UID/04413/2025) and the Associated Laboratory in Translation and Innovation Towards Global Health REAL (LA/P/0117/2020). Additional support was provided by the DrugsForNg project Ref. UID/04413/2020 – DrugsForNg, and the DREBI Project Ref. 2022.07931.PTDC (doi: 10.54499/2022.07931.PTDC). Publisher Copyright: Copyright © 2026 Marques, Costa and Rodrigues.
Palavras-chave
Candida albicans drug repurposing efflux inhibitors efflux pumps phenotypic screening Microbiology Immunology Microbiology (medical) Infectious Diseases SDG 3 - Good Health and Well-being