Antifungal Mechanisms and Drug Development in Yeast Systems

Fungal pathogens of the Saccharomycotina subphylum, notably Candida species and the model yeast Saccharomyces cerevisiae, present significant challenges in medicine and agriculture. The close evolutionary relationship between fungi and their human hosts limits the number of selective drug targets, necessitating innovative strategies. Research in yeast systems has elucidated multiple mechanisms of action, including interference with ergosterol biosynthesis, disruption of cell‐wall assembly via β-glucan or chitin inhibition, and induction of oxidative stress through reactive oxygen species (ROS). Advances in high-throughput phenotypic screening, structural biology and engineered yeast strains have revealed resistance pathways such as efflux pump upregulation and biofilm formation. In parallel, synthetic small molecules, cyclic peptides and lipopeptides have emerged as promising leads, frequently combining membrane permeabilisation with mitochondrial dysfunction and cell-cycle arrest. These interdisciplinary efforts underpin a development pipeline aimed at producing broad-spectrum, low-toxicity antifungals to combat invasive candidiasis in immunocompromised patients and mitigate azole resistance in agricultural settings.

Research from Nature Portfolio

Semisynthetic derivatives of a macrolide scaffold have been optimised for potent activity against Candida albicans. The lead compound stimulates intracellular ROS accumulation, causing oxidative damage to fungal membranes, depletion of glutathione, and loss of mitochondrial membrane potential. Concurrent downregulation of hyphal-associated virulence factors and inhibition of filamentous growth were observed in vitro. In a murine model of disseminated candidiasis, treatment prolonged survival and reduced fungal burden. This work establishes a structure–activity relationship framework for refining macrolide analogues as novel antifungal therapeutics.

Antifungal Mechanisms and Drug Development in Yeast Systems publication trend

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

Technical terms

Reactive oxygen species (ROS): chemically reactive oxygen derivatives that damage lipids, proteins and nucleic acids.

Minimum inhibitory concentration (MIC): lowest concentration of an antifungal agent that prevents visible growth of a microorganism in vitro.

Membrane permeabilization: loss of cell-membrane integrity leading to uncontrolled passage of molecules across the lipid bilayer.

Lipopeptide: molecule combining lipid chains and peptide sequences, commonly targeting microbial membranes for disruption.

Ergosterol: principal sterol in fungal cell membranes and the binding site for polyene antifungals.

References

1. A semisynthetic borrelidin analogue BN-3b exerts potent antifungal activity against Candida albicans through ROS-mediated oxidative damage. Scientific Reports (2020).
2. Design, Synthesis, and Biological Evaluation of N′-Phenylhydrazides as Potential Antifungal Agents. International Journal of Molecular Sciences (2023).
3. Functional Characterization of a Bacillus-Derived Novel Broad-Spectrum Antifungal Lipopeptide Variant against Candida tropicalis and Candida auris and Unravelling Its Mode of Action. Microbiology Spectrum (2023).
4. Cyclic Peptides with Antifungal Properties Derived from Bacteria, Fungi, Plants, and Synthetic Sources. Pharmaceuticals (2023).