Integrative computational-experimental discovery and translation of antifungal peptides for multidrug-resistant fungi

Multidrug-resistant fungal infections caused by Candida and Aspergillus species have become one of the major global health concerns, especially among immunocompromised individuals. The small number of antifungals available and the rapid emergence of resistance to azoles, echinocandins and polyenes underscore the urgent need to develop alternative therapeutic strategies with different mechanisms of action. Antifungal peptides (AFPs) have attracted increasing attention as promising candidates due to their broad-spectrum activity, multimodal mechanisms of action, and their low likelihood of resistance development. This review presents a thorough and holistic summary of the research on AFPs that target clinically significant drug-resistant fungi such as Candida auris, azole-resistant Candida albicans, and triazole-resistant Aspergillus fumigatus. We review the structural and physicochemical properties of AFPs and address their various antifungal mechanisms, which include membrane disruption, oxidative stress induction, and disruption of intracellular homeostasis, as well as biofilm inhibition. We further highlight an emerging computational-experimental pipeline to discover and optimize AFPs, combining sequence mining, machine learning-based screening, molecular docking, molecular dynamics simulations, and in vitro and in vivo validation. We also explore the major translational challenges, such as hemolytic toxicity, proteolytic instability, pharmacokinetic constraints, manufacturing complexity, regulatory concerns, and sustainable peptide manufacturing strategies, and discuss advanced delivery systems (e.g., liposomes, PLGA nanoparticles, chitosan-based systems, and hydrogels) to improve therapeutic efficacy and stability. In summary, this review proposes an integrated translational development framework that connects computational design, experimental validation, and delivery engineering, thereby positioning AFPs as a promising next-generation strategy in the fight against multidrug-resistant fungal infections.