Integrated Review of Antifungal Resistance: Mechanistic Insights, Clinical Challenges and Therapeutics Intervention

Deeply invasive fungal infections are emerging as an increasingly substantial worldwide healthcare challenge, especially for medically compromised and individuals with weakened immune systems. The aforementioned infectious conditions are challenging to address because clinical diagnosis is often prolonged and mycotic organisms swiftly acquire resistance against commonly used drug classes such as azoles, polyenes, and echinocandins. In the present review, we explore the molecular and cellular mechanisms responsible for antifungal resistance, incorporating modifications at drug target sites, overexpression of targets, upregulation of stress‑response pathways like Hsp90 and calcineurin, genomic flexibility, and drug efflux through transporters such as ABC and MFS families. We also discuss diagnostic strategies, from traditional methods to modern molecular and biomarker‑based assays. Special emphasis is devoted to WHO‑listed highest-priority pathogens such as Candida auris, and the therapeutic innovations currently being investigated to combat them. These involve next‑generation antifungals (fosmanogepix, ibrexafungerp, rezafungin), naturally derived compounds, combination therapies, biologics, and nanotechnology‑based delivery systems. Ultimately, strengthening patient outcomes worldwide will require integrating sophisticated diagnostic approaches with these emerging treatment to counteract existing clinical challenges.