WHO Critical Priority Fungi: A Comprehensive Review of Antifungal Resistance, Emerging Therapeutic Strategies, and the Potential of Antifungal Peptides.

Extensive clinical studies have convincingly demonstrated that fungal infections constitute a mounting global health concern. Candida albicans, C. auris, Aspergillus fumigatus, and Cryptococcus neoformans were classified by the WHO as critical priority fungi due to their widespread prevalence, high mortality rates associated with invasive mycoses, and the increasing spread of resistant strains. The currently available antifungal arsenal, comprising four major classes (azoles, polyenes, echinocandins, and flucytosine), is critically insufficient. Resistance to these agents is escalating worldwide, while the approval of new drugs remains alarmingly slow. This review provides a comprehensive overview of the molecular mechanisms underlying resistance to conventional and emerging antimycotics in critical priority fungi, including recently approved and investigational agents such as oteseconazole, rezafungin, ibrexafungerp, fosmanogepix, and olorofim. It examines current strategies to overcome resistance, including combination therapy, drug repurposing, targeted delivery, antibiofilm approaches, immunotherapy, and the application of natural antifungal compounds. Special emphasis is placed on antifungal peptides (AFPs) derived from plants, animals, bacteria, and fungi, along with their synthetic analogs, all of which have demonstrated efficacy against critical priority fungi. The review primarily focuses on the molecular targets of AFPs and on the development of fungal resistance under prolonged exposure, compared with conventional antifungals, in order to evaluate their potential as prototypes for next-generation antimycotics.