New Research Uncovers Elusive Target of Antifungal Agent

A research team in Japan has uncovered the mechanism underlying the antifungal activity of theonellamide (TNM), a bioactive compound found in a species of marine sponge.

The finding, reported in Nature Chemical Biology, provides new insights toward the development of antifungal drugs, with broader applications to drug analysis in areas such as cancer research.

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Both humans and fungus, unlike bacteria, belong to the same family of eukaryotes. Designing drugs that target fungal cells poses serious challenges due to their similarity to human cells at the molecular level. The difficulty of this task results in toxic side effects and a shortage of effective antifungal agents.

To avoid damaging human cells, the new drugs exploit differences between mammalian and fungal cells.

The research team, headed by scientists at the RIKEN Advanced Science Institute, Japan, set out to tackle this problem by investigating the antifungal activity of theonellamides (TNMs), which are bicyclic peptides found in the marine sponge Theonella, on the fission yeast Schizosaccharomyces pombe.

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Antifungal activity in TNMs, the researchers showed, is different from other antifungals, which cause damage by impairing wall synthesis. Instead, TNMs damage fungal cells by abnormally promoting cell component synthesis.

Combining chemical-genetic profiling and biochemical and cellular analysis, they deduced that TNMs bind to a class of lipid molecules (3β-hydroxysterols) in the cell membrane to induce overproduction of 1,3-β-D-glucan, a component of the cell wall.

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TNMs act by targeting a class of lipids, including ergosterol, and not proteins as previously deduced.

Thus they represent an entirely new class of sterol-binding molecules, offering a new direction in the development of antifungal agents and a powerful tool for drug analysis.

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