Each year, invasive fungal infections sicken an estimated 2
million people worldwide and kill nearly 800,000 – but a team of international
scientists have discovered a new approach for antifungal drug treatments.
Researchers from USC and France identified that a
gene-regulating protein, Bdf1, is critical for the survival of the pathogenic
fungus, Candida albicans.
“We have shown that Bdf1 is an important new target for
drug design,” said Charles McKenna, a senior author of the study who is a
professor of chemistry and pharmaceutical sciences in the USC Dornsife College
of Letters, Arts and Sciences. “Our findings show that compounds that bind
to this target will disrupt the growth of the fungus, opening the way to novel
drug treatments for fungal disease.”
The French scientists who led the study with McKenna were
Jérôme Govin and Carlo Petosa, both at the University of Grenoble Alpes.
Rising health threat
The fungus, C. albicans, is an aggressive pathogen
that in healthy individuals is normally held in check by the immune system.
However, people with a weakened immune system, including patients who have
cancer, HIV or autoimmune diseases, are susceptible to the infection, which can
be life-threatening, McKenna said.
The team’s findings, published on May 18 in the journal Nature
Communications, may prove timely. Fungal infections such as candidiasis are
increasingly resistant to drug treatments. Each year, an estimated 46,000
patients in the United States become infected with invasive candidiasis,
according to the Centers for Disease Control and Prevention.
“When susceptible people develop candida infections,
the fungus may enter the bloodstream. If treatment is unsuccessful, it has a
very high mortality rate – in the 40 percent range,” McKenna said.
“We have a very limited number of drugs that are effective in treating
such systemic infections. Unfortunately, like many other pathogens, C.
albicans is increasingly resistant to the few available drugs, raising the
stakes for patients, and fresh approaches are urgently needed.”
Disrupting fungal gene expression
Many scientists are studying alternative approaches for
possible treatments to diseases such as cancer by manipulating gene expression.
The USC-Grenoble team is the first to prove that this approach is feasible to
target fungal infections.
“The idea is that if you shut down this specific
protein, Bdf1, you totally disrupt the whole process of gene expression and it
becomes impossible for the fungus to grow,” said Govin. “If you knock
out the gene that makes the Bdf1 protein, then the fungus doesn’t grow.
Moreover, the fungus is no longer virulent when injected into mice.”
The challenge for the scientists was finding a compound that
shut down the Bdf1 protein without mistakenly affecting any similar proteins in
“Using a technique called X-ray crystallography, we
showed that the fungal Bdf1 protein and corresponding human proteins are very
different at the atomic level,” said Petosa. “This showed that
compounds could specifically inhibit the fungal protein without affecting the
human bromodomain proteins.”
By screening a large library of chemical compounds at the California
Institute for Biomedical Research, the researchers have already identified
one compound in particular that selectively inhibits Bdf1. The finding holds
great promise for future drug development.
“It shows that a whole new class of antifungal drugs is
possible,” said McKenna.
The work was supported by French grants, including from the
Agence National de Recherche and French FACE foundation, and an estimated
$454,000 from a National
Institutes of Health grant to McKenna (IR21AI113704), which provided one third
of the funds for the study.