Targeting Fungal Hsp90: Role of Flavonoids in Overcoming Antifungal Resistance

Abstract

The growing prevalence of antifungal resistance has emerged as a significant global health challenge, reducing the effectiveness of existing antifungal medications and creating an urgent need for innovative therapeutic approaches. Heat shock protein 90 (Hsp90), an ATP-dependent molecular chaperone, plays a crucial role in fungal survival by regulating growth, stress adaptation, virulence, and antifungal resistance through the stabilization of essential signaling proteins involved in cellular homeostasis. Therefore, Hsp90 has gained considerable attention as a potential molecular target for antifungal drug discovery. Flavonoids, a structurally diverse class of naturally occurring polyphenolic compounds, possess a wide range of pharmacological properties, including antioxidant, anti-inflammatory, antimicrobial, and antifungal activities. This review discusses the biological importance of flavonoids and examines their potential to overcome antifungal resistance by targeting Hsp90. Available evidence indicates that flavonoids may improve the therapeutic efficacy of conventional antifungal agents by regulating fungal stress-response mechanisms, suppressing efflux pump activity, disrupting cell wall and membrane integrity, and potentially binding to the conserved ATP-binding pocket of Hsp90. In addition, the review emphasizes the usefulness of molecular docking as an in silico screening tool for identifying flavonoids with strong binding affinity toward fungal Hsp90, thereby supporting future experimental validation. Overall, targeting fungal Hsp90 with flavonoid-based compounds represents a promising strategy for managing drug-resistant fungal infections and may contribute to the development of safer and more effective antifungal therapies.