Antifungal Drug Discovery Against Priority Fungal Pathogens: Natural Compounds, Synthetic Scaffolds, and Emerging Resistance Mechanisms

Invasive fungal infections cause substantial morbidity and mortality worldwide, yet they remain underrepresented in drug development pipelines. Pathogens classified in the World Health Organization 2022 fungal priority pathogens list, particularly critical priority species such as Candida auris, Aspergillus fumigatus, and Cryptococcus neoformans, alongside high priority species such as Histoplasma capsulatum, present acute threats to immunocompromised and critically ill patients. The intersection of antifungal drug discovery and the COVID-19 pandemic reveals a critical synergistic crisis where viral infection exacerbates the threat of invasive fungal diseases (IFDs), thereby accelerating the urgency for novel therapeutic scaffolds. The existing systemic antifungal arsenal relies on four primary drug classes: polyenes, azoles, echinocandins, and pyrimidine analogues. Each class carries clinical limitations, including host toxicity, narrow activity spectra, or restricted routes of administration. Because fungi share core eukaryotic pathways with their mammalian hosts, selective chemical targeting remains difficult, making the discovery of molecules with distinct modes of action a clinical imperative.The antifungal drug discovery field faces a specific set of challenges that have slowed progress for decades. The number of clinically validated fungal targets remains small. Resistance is emerging across all major drug classes, driven by mechanisms including target gene mutations, upregulation of efflux transporters, and biofilm-associated tolerance. Natural compounds, including terpenoids, phenolics, alkaloids, and marine-derived metabolites, have shown antifungal activity in experimental settings, but systematic pharmacological characterization is still lacking for most. Structure-guided design approaches targeting ergosterol biosynthesis enzymes, cell wall components, or fungal virulence determinants are generating early-stage leads that deserve wider attention. This Research Topic brings together work across these areas to build a clearer picture of where the field stands and where the most promising directions lie. The aim is not to survey the literature broadly, but to gather focused, evidence-based contributions that address specific gaps in mechanistic understanding, preclinical validation, or translational development.Contributions should address one or more of the following: antifungal activity of natural or synthetic compounds with defined mechanisms of action; resistance mechanisms in WHO priority fungal pathogens; structure-activity relationship studies; antifungal combination approaches; in vitro or in vivo preclinical models; computational methods applied to antifungal target identification or compound screening; and formulation or delivery strategies designed to improve the pharmacological profile of existing or experimental agents. Studies centered on C. auris, A. fumigatus, C. neoformans, Candida species, and other WHO-listed pathogens are particularly relevant. Original research articles, systematic reviews, narrative reviews, mini-reviews, perspectives, and methods articles are all welcome. Authors are encouraged to situate their work within the context of unmet clinical need or current resistance trends. Topic editors: VIKAS KUMAR, Sachin Gulati, Dr.Manoj Singh, Anil Kumar Sharma Source: https://www.frontiersin.org/research-topics/85829/antifungal-drug-discovery-against-priority-fungal-pathogens-natural-compounds-synthetic-scaffolds-and-emerging-resistance-mechanisms