Molecular Mechanisms, Diagnosis, and Therapeutic Strategies of Antifungal Resistance in Filamentous Fungi

Antifungal resistance in filamentous fungi has emerged as a major threat to global public health, posing a serious challenge particularly to immunocompromised populations. This review provides a systematic overview of the molecular mechanisms, diagnostic approaches, and clinical therapeutic strategies for antifungal resistance in filamentous fungi, with a focus on Aspergillus fumigatus, Fusarium spp., Mucorales, and Scedosporium spp./Lomentospora prolificans. Resistance mechanisms can be broadly categorized as intrinsic resistance and acquired resistance. Intrinsic resistance arises from species-specific genetic traits, such as structural differences in target sites, constitutive overexpression of efflux pumps, and metabolic pathway redundancy. Acquired resistance develops under drug pressure through target gene mutations (e.g., hotspot mutations and promoter tandem repeats in CYP51A), efflux pump overexpression, biofilm formation, and epigenetic regulation. For diagnosis, conventional culture and antifungal susceptibility testing remain the gold standard; however, molecular techniques—including MALDI-TOF MS, targeted resistance gene PCR, and metagenomics—are substantially improving detection efficiency. Therapeutic strategies should be stratified based on antifungal susceptibility testing results and species identification. Precision dosing guided by therapeutic drug monitoring, combination therapy, and the introduction of novel agents (including isavuconazole, rezafungin, fosmanogepix, and olorofim) are progressively improving clinical outcomes. Looking ahead, global surveillance and multisectoral collaboration are essential to deepen our understanding of resistance evolution, accelerate the clinical translation of novel diagnostic and therapeutic tools, and curb the global spread of resistance.