Antifungal resistance: Emerging mechanisms and implications (Review)

Abstract

Antifungal resistance is a growing concern in clinical medicine, driven by the increasing incidence of fungal infections and the limited arsenal of effective antifungal drugs. This resistance is achieved by intrinsic mechanisms, such as ineffective drug‑target binding, high efflux pump activity and unique cell wall and membrane composition, as well as acquired mechanisms, including genetic mutations, gene duplication, transposon insertions, aneuploidies and loss of heterozygosity. Antifungal tolerance, characterized by subpopulations of fungal cells that persist and proliferate even at high drug concentrations, complicates treatment. The present review aimed to examine the genetic, physiological and epigenetic factors that contribute to antifungal resistance and tolerance. Understanding these mechanisms may enable the development of novel antifungal therapies and effective diagnostic strategies to combat the increasing threat of resistant fungal infection. Advanced diagnostic tools and combination therapies are key for managing resistant infections and ongoing research into these mechanisms may enhance the ability to mitigate antifungal resistance.

Keywords: antifungal; epigenetic; infectious disease; resistance.

Figure 1.

Genetic mechanisms of acquired antifungal resistance in pathogenic fungi. (A) Point mutation in Candida albicans. A single nucleotide substitution in the ERG11 gene (such as Y132H) leads to amino acid changes in lanosterol 14α-demethylase, decreasing azole binding and conferring fluconazole resistance. (B) Gene duplication in Nakaseomyces glabratus. Duplication of resistance-related genes, such as ERG11, leads to gene upregulation and increased tolerance to azoles. (C) Transposon insertion in Cryptococcus neoformans. Insertion of mobile genetic elements such as CNL1 transposon disrupts pathways involved in calcineurin signalling, contributing to resistance against calcineurin inhibitors (for example, FK506 and rapamycin). (D) LOH in Candida albicans. LOH converts a heterozygous MDR1 allele into a homozygous recessive state, unmasking resistance-conferring mutations and leading to azole resistance. (E) Aneuploidy in Candida neoformans. Duplication of chromosomes (such as those carrying AFR1, an azole efflux transporter gene) under antifungal stress leads to increased drug efflux and resistance. (F) Hypermutator lineage in Nakaseomyces glabratus. Defects in DNA repair machinery result in elevated mutation rates. Some hypermutator strains acquire adaptive mutations that confer resistance, while others do not. H, hypermutator; WT, wild-type; LOH, loss of heterozygosity; CNL1, Cryptococcus neoformans LINE-1-like element; MDR, Multidrug Resistance; AFR, azole fungal resistance. This figure was created using Biorender: https://BioRender.com/or7ka94”