Antifungal Drug Mechanisms in Pathogenic Yeasts

Antifungal therapies against pathogenic yeasts exploit a handful of conserved cellular processes to disrupt fungal viability while sparing the human host. The principal targets involve the fungal cell membrane, where inhibition of ergosterol biosynthesis compromises membrane integrity and fluidity; the cell wall, wherein blockade of β-glucan synthase or interference with cell wall assembly weakens structural rigidity; and intracellular enzymes such as DNA topoisomerases, whose inhibition impedes genome replication and transcription. Resistance mechanisms often centre on upregulation of efflux pumps belonging to the ATP-binding cassette and major facilitator superfamilies, which reduce intracellular drug accumulation, as well as mutations in target enzymes that decrease drug binding. Recent efforts focus on novel chemical scaffolds that circumvent existing resistance pathways by avoiding efflux, combining multiple modes of action or targeting alternative essential enzymes. Advances in structural biology, transcriptomics and in vivo models have accelerated the discovery of compounds with favourable selectivity indices and encouraged combination strategies to enhance efficacy and forestall resistance development.

Research from Nature Portfolio

Novel xanthone derivatives have been shown to exert potent anticandidal activity and to evade primary fungal efflux systems by exhibiting low affinity for key ABC and major facilitator pumps. These compounds display a predominantly fungicidal mode of action, reducing the likelihood of persistent infections and resistant subpopulations, and act by inhibiting yeast topoisomerase II activity. In parallel, heteropolytungstate clusters have re-emerged as promising candidates that disrupt ergosterol biosynthesis, leading to membrane damage and transcriptional upregulation of ergosterol pathway genes. In murine models of systemic candidiasis, the most active heteropolytungstate reduced fungal burden and clinical morbidity without overt toxicity, underscoring the translational potential of metallodrug therapies.

Antifungal Drug Mechanisms in Pathogenic Yeasts publication trend

The graph below shows the total number of articles in antifungal drug mechanisms in pathogenic yeasts across all publications each year (not limited to Nature Index journals).

Technical terms

Ergosterol: A sterol unique to fungal cell membranes that maintains membrane structure and function.

β-Glucan synthase: An enzyme complex responsible for the synthesis of β-glucan polymers in the fungal cell wall.

ATP-binding cassette (ABC) transporters: A family of membrane proteins that use ATP hydrolysis to efflux diverse substrates, including antifungal drugs.

Major facilitator superfamily (MFS): A group of secondary transporters that mediate drug efflux via proton-driven conformational changes.

Topoisomerase II: An essential enzyme that introduces transient double-strand breaks to resolve DNA supercoiling during replication and transcription.

References

1. Xanthone synthetic derivatives with high anticandidal activity and positive mycostatic selectivity index values. Scientific Reports (2023).
2. In vitro and in vivo antifungal activities and mechanism of heteropolytungstates against Candida species. Scientific Reports (2017).
3. Identification and characterization of a novel antifungal compound tubeimoside I targeting cell wall. Microbiology Spectrum (2024).
4. Review and Current Perspectives on DNA Topoisomerase I and II Enzymes of Fungi as Study Models for the Development of New Antifungal Drugs. Journal of Fungi (2024).