Fungal Secondary Metabolites in Antifungal Drug Development

Fungal secondary metabolites are structurally diverse small molecules produced by fungi that are not essential for primary growth but play key roles in ecological interactions. Over the past seven decades, these compounds have formed the backbone of antifungal chemotherapy, yielding major drug classes such as polyenes, echinocandins and azoles. Renewed interest in this reservoir has been driven by the rise of resistant fungal pathogens and a dwindling pipeline of novel agents. Modern strategies combine genome mining, chemical profiling and synthetic biology to unearth cryptic biosynthetic pathways, enabling the discovery of new scaffolds and the optimisation of lead molecules. Advances in analytical chemistry and computational modelling now permit rapid dereplication of known compounds and in silico prediction of binding modes against validated fungal targets. Concurrent progress in fermentation engineering and heterologous expression has improved yields of rare metabolites, while medicinal chemistry refines potency, selectivity and pharmacokinetics. Together, these interdisciplinary approaches aim to address global health threats posed by invasive mycoses and to expand the therapeutic armamentarium with agents that overcome existing resistance mechanisms.

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Fungal Secondary Metabolites in Antifungal Drug Development publication trend

The graph below shows the total number of articles in fungal secondary metabolites in antifungal drug development across all publications each year (not limited to Nature Index journals).

Technical terms

Secondary metabolite: A non‐essential small molecule produced by an organism that often mediates ecological interactions and can possess pharmacological activity.

Polyketide: A diverse class of secondary metabolites assembled by polyketide synthase enzymes, known for their complex carbon skeletons and therapeutic properties.

Endophyte: A microorganism, often a fungus, that lives within plant tissues without causing disease and can produce bioactive compounds.

Biosynthetic gene cluster (BGC): A contiguous set of genes that together encode the enzymes required to produce a specific secondary metabolite.

One‐strain–many‐compounds (OSMAC) approach: A strategy that alters cultivation parameters (medium composition, pH, aeration) to induce a single fungal strain to express multiple secondary metabolites.

References

1. Antifungal Activity of Menisporopsin A against Relevant Plant Pathogens. Journal of Fungi (2024).
2. Antifungal Secondary Metabolites Produced by the Fungal Endophytes: Chemical Diversity and Potential Use in the Development of Biopesticides. Frontiers in Microbiology (2021).
3. OSMAC Strategy Integrated with Molecular Networking for Accessing Griseofulvin Derivatives from Endophytic Fungi of Moquiniastrum polymorphum (Asteraceae). Molecules (2021).