Inhibitory effects of berberine on fungal growth, biofilm formation, virulence, and drug resistance as an antifungal drug and adjuvant with prospects for future applications.

Berberine (BBR), an isoquinoline alkaloid found in medicinal plants such as Coptidis rhizoma, Berberis sp., and Hydrastis canadensis, is a distinctive compound known for its dual ability to exhibit broad-spectrum antifungal activity while offering beneficial effects to the host. These attributes make it a highly valuable candidate for antifungal therapy and as an antibiotic adjuvant. This review provides a comprehensive evaluation of BBR's antifungal properties, focusing on its in vitro and in vivo activity, underlying mechanisms, and its influence on fungal pathogenicity, including virulence, biofilm formation, and resistance. Additionally, the antifungal potential of BBR extracts, derivatives, and nanoformulations is examined in detail. BBR demonstrates fungicidal effects through multiple mechanisms. It targets critical fungal components such as mitochondria, cell membranes, and cell walls, while also inhibiting enzymatic activity and transcription processes. Furthermore, it suppresses the expression of virulence factors, effectively diminishing fungal pathogenicity. Beyond its direct antifungal activity, BBR exerts beneficial effects on the host by modulating gut microbiota, thereby bolstering host defenses against fungal infections and reducing potential adverse effects. BBR's interaction with conventional antifungal drugs presents a unique complexity, particularly in the context of resistance mechanisms. When used in combination therapies, conventional antifungal drugs enhance the intracellular accumulation of BBR, thereby amplifying its antifungal potency as the primary active agent. These synergistic effects position BBR as a promising candidate for combination strategies, especially in addressing drug-resistant fungal infections and persistent biofilms. As antifungal resistance and biofilm-associated infections continue to rise, the multifaceted properties of BBR and its advanced formulations highlight their significant therapeutic potential. However, the scarcity of robust in vivo and clinical studies limits a full understanding of its efficacy and safety profile. To bridge this gap, future investigations should prioritize well-designed in vivo and clinical trials to thoroughly evaluate the therapeutic effectiveness and safety of BBR in diverse clinical settings. This approach could pave the way for its broader application in combating fungal infections.