Repositioning Antimicrobial Peptides Against WHO-Priority Fungi

The growing threat of fungal infections, particularly in immunocompromised individuals, is exacerbated by the limited number of antifungal drug classes, increasing resistance rates, and complex hostpathogen interactions. In response to this public health concern, the World Health Organization published its first list of fungal priority pathogens, including C. auris, A. fumigatus, C. neoformans, and C. albicans. These species exhibit multidrug resistance, virulence plasticity, and enhanced biofilm-forming capacity, which contributes to antifungal tolerance and complicates treatment outcomes. Antimicrobial peptides (AMPs) have emerged as promising alternatives due to their broad-spectrum activity, rapid membrane-disrupting mechanisms, and low propensity to induce resistance. This review provides an in-depth analysis of AMP-based antifungal strategies, integrating insights from structureactivity relationships, molecular engineering, and targeted delivery systems. Strategies such as peptide hybridization, cyclization, PEGylation, and nanoparticle conjugation are examined to enhance stability, specificity, and pharmacokinetics. Opportunities for rational AMP design are also discussed, leveraging computational toolsincluding machine learning and deep learning approachesalongside immunoproteomic targeting. Together, these multidisciplinary advances underscore the potential of AMPs as next-generation therapeutics against critical fungal pathogens. Nonetheless, clinical translation remains challenging, requiring continued investment in formulation science, regulatory alignment, and translational development pipelines.