ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Ethnopharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1643472
This article is part of the Research TopicTreatment of Infectious Diseases with Bioactive Compounds from Medicinal Plants: Their Mechanisms and Applications - Volume IIView all 11 articles
Menthol-Thymol NADES as a fungicidal and chemosensitizing agent against multidrug-resistant Candida albicans: ROS induction, efflux pump inhibition, and synergy with fluconazole
Provisionally accepted
Melisa Negro1,2
Pamela Soledad Bustos1,2
Lautaro Bellezze1
Maria Gabriela Ortega1,2
Javier Echeverria3*María Fernanda Silva4
MARIANA ANDREA PERALTA1,2- 1Farmacognosia, Departamento de Ciencias Farmacéuticas, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Cordoba, Argentina
- 2Unidad de Investigación y Desarrollo en Tecnología Farmacéutica (UNITEFA-CONICET), Ciudad Universitaria, Cordoba, Argentina
- 3Departamento de Ciencias del Ambiente, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile
- 4Grupo de Química Analítica Verde (GQAV), Instituto de Biología Agrícola de Mendoza (IBAM-CONICET). Facultad de Ciencias Agrarias-Universidad Nacional de Cuyo (FCA-UNCuyo), Mendoza, Argentina
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The increasing prevalence of azole-resistant Candida albicans (RCa) poses a critical therapeutic challenge, necessitating innovative antifungal approaches.Natural Deep Eutectic Solvents (NADES), derived from natural metabolites such as terpenes, provide a promising and sustainable platform for delivering bioactive compounds with intrinsic pharmacological properties.Purpose: This study evaluated a eutectic system composed of menthol and thymol (MT NADES, 1:1 molar ratio) for its antifungal efficacy against a multidrug-resistant clinical C. albicans strain. diffusion assays (FICI: 0.2839). Mechanistic studies revealed increased intracellular ROS, supporting oxidative stress as a key antifungal mechanism. Additionally, MT NADES at half its MIC enhanced Nile red retention tenfold over the efflux pump inhibitor tacrolimus (100 µM), indicating strong inhibition of MDR-related transporters.These findings highlight MT NADES as a promising chemosensitizing agent with superior efficacy over its individual components.These findings underscore the therapeutic potential of menthol-thymol NADES as a multifunctional, plant-derived antifungal strategy capable of overcoming multidrug resistance mechanisms and potentiating azole efficacy in C. albicans.
Keywords: Ecopharmacognosy, Natural deep eutectic solvents, Terpenes, Antifungal, multidrug resistance, Candida albicans, Efflux pump inhibition, Chemosensitizer
Received: 09 Jun 2025; Accepted: 23 Jul 2025.
Copyright: © 2025 Negro, Bustos, Bellezze, Ortega, Echeverria, Silva and PERALTA. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Javier Echeverria, Departamento de Ciencias del Ambiente, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.