Combination of fluconazole with natural compounds: A promising strategy to manage resistant Candida albicans infections

Patients admitted to the intensive care unit or immunocompromised patients frequently develop fungal infections. Candida albicans (C. albicans) is the pathogenic fungus responsible for most invasive fungal infections. Fluconazole (FLC) is the most widely used antifungal agent in clinical practice due to its effectiveness and low cost. However, due to its widespread use, C. albicans is becoming increasingly resistant to FLC. This increase in resistance poses a significant challenge for antifungal treatments. Various attempts have been made to reverse the resistance of C. albicans to FLC, including combinations with natural compounds with low toxicity, low cost, and high antifungal efficacy. Furthermore, various natural compounds have in vitro and in vivo synergistic effects with FLC against C. albicans, particularly when treating resistant isolates. This review summarises natural compounds that, when combined with FLC, exhibit synergistic effects against C. albicans. These combinations were identified through a comprehensive search of PubMed, Web of Science, and Embase databases until March 2023. Forty-eight natural antifungal compounds with potential clinical applications were identified. The most common mechanisms underlying their synergistic effects include inhibition of drug efflux, induction of mitochondrial dysfunction, and accumulation of reactive oxygen species (ROS). The combination of FLC with natural compounds provides potential new therapeutic options against C. albicans infections and offers insights into reversing resistance.