Antifungals: mechanism of action, resistance, and therapeutic perspectives

Fungal infections represent a growing challenge to global public health, driven by the increasing number of immunocompromised patients and the emergence of strains resistant to currently available antifungal drugs. It is estimated that more than 1.6 million deaths per year are attributable to fungal diseases and that the global incidence of invasive fungal infections exceeds 6 to 65 million cases annually. Despite advances in diagnosis and treatment, the pharmacological repertoire against pathogenic fungi remains limited, favoring the emergence and dissemination of resistance. This paper will review the main classes of antifungal agents used in clinical practice, their mechanisms of action, and the molecular basis of resistance in medically important genera, including Aspergillus, Blastomyces, Cryptococcus, Coccidioides, Paracoccidioides, Histoplasma, and Sporothrix. Particular attention is given to pathogens whose antifungal susceptibility patterns and resistance mechanisms remain insufficiently characterized. It will examine processes such as alteration or overexpression of therapeutic targets, activation of efflux pumps, biofilm formation, genomic plasticity, and adaptive mechanisms that promote fungal tolerance. In addition, the epidemiological and clinical implications of antifungal resistance will be discussed, along with emerging strategies for its control, including the development of new compounds, combination therapies, and immunomodulatory approaches. This review aims to provide a current and comprehensive overview of the mechanisms underlying resistance and the therapeutic alternatives under development, emphasizing the need for interdisciplinary efforts to confront the growing threat posed by resistant mycoses.