Molecular mechanisms governing antifungal drug resistance

Fungal pathogens are a severe public health problem. The leading causative agents of systemic fungal infections include species from the Candida, Cryptococcus, and Aspergillus genera. As opportunistic pathogens, these fungi are generally harmless in healthy hosts; however, they can cause significant morbidity and mortality in immunocompromised patients. Despite the profound impact of pathogenic fungi on global human health, the current antifungal armamentarium is limited to only three major classes of drugs, all of which face complications, including host toxicity, unfavourable pharmacokinetics, or limited spectrum of activity. Further exacerbating this issue is the growing prevalence of antifungal-resistant infections and the emergence of multidrug-resistant pathogens. In this review, we discuss the diverse strategies employed by leading fungal pathogens to evolve antifungal resistance, including drug target alterations, enhanced drug efflux, and induction of cellular stress response pathways. Such mechanisms of resistance occur through diverse genetic alterations, including point mutations, aneuploidy formation, and epigenetic changes given the significant plasticity observed in many fungal genomes. Additionally, we highlight recent literature surrounding the mechanisms governing resistance in emerging multidrug-resistant pathogens including Candida auris and Candida glabrata. Advancing our knowledge of the molecular mechanisms by which fungi adapt to the challenge of antifungal exposure is imperative for designing therapeutic strategies to tackle the emerging threat of antifungal resistance.