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.
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.
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
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.
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.