Fungal Iron-Sulfur Clusters (Fungal Fe-S clusters)

Iron-sulfur (Fe-S) clusters are ancient, ubiquitous, and versatile prosthetic groups composed of iron and sulfide ions, essential for a wide array of biological processes in fungi. These clusters are integral components of many fungal proteins, where they facilitate electron transfer, catalyze enzymatic reactions, regulate gene expression, and play a critical role in iron homeostasis. In pathogenic fungi, the proper functioning and biogenesis of Fe-S clusters are crucial for their survival, growth, and virulence within a host, making them attractive targets for antifungal drug development. Therapeutic strategies often focus on disrupting the complex biogenesis pathways of these clusters or chelating the iron necessary for their formation. However, a significant challenge in targeting fungal Fe-S clusters lies in their high conservation across all domains of life, including humans, raising concerns about potential off-target toxicity to human cells. Despite these challenges, the essentiality of Fe-S clusters for fungal viability continues to drive research into novel antifungal compounds that can selectively interfere with these vital cofactors or their assembly machinery in fungal pathogens.

Other names

Fungal Fe-S centersFungal ISCsIron-sulfur clusters in fungi

Drugs targeting fungal iron-sulfur clusters primarily act through iron chelation, which sequesters iron and prevents the assembly of these essential cofactors. They can also disrupt the iron-sulfur cluster biogenesis pathways (ISC, SUF, CIA systems) that are crucial for their formation and delivery to fungal proteins. Additionally, some compounds may directly interact with or alter the clusters, or induce their alteration indirectly through the generation of reactive oxygen species.