UW–Madison researchers identify therapeutic target for dangerous fungal infections

The discovery could prevent against Candida auris, a drug-resistant fungus and global public health threat that spreads in hospitals and other care settings.

A multidisciplinary team of researchers at the University of Wisconsin-Madison has identified a promising new therapeutic candidate against Candida auris, an emerging fungal pathogen that has alarmed health officials worldwide because of its ability to resist multiple antifungal drugs and spread rapidly through hospitals and care facilities.

"It's a global public health threat," says Jeniel Nett, a professor in the Department of Medicine at the UW School of Medicine and Public Health. "Candida auris is the first fungus to spread in hospitals and cause serious disease."

With funding from the National Institutes of Health, Nett led a team that closely studied the yeast in search of any weaknesses that could be exploited in the fight against it. The need is urgent; there are three major classes of antifungal drugs, and certain strains of Candida auris are resistant to all three of them.

While the fungus's presence on skin isn't itself life-threatening, there are many opportunities for internal exposure - whether through surgery, a catheter or other medical devices - where it can pose grave danger. Between 30 to 60% of patients who develop a Candida auris infection die, usually due to sepsis after the fungus enters their bloodstream after getting inside the body.

Most Candida auris infections respond to an intravenous medication that's available, but even that is showing signs of vulnerability.

"There have been reports of Candida strains developing resistance to that, leading to a very serious infection," says Nett.

Studying both synthetic conditions and human skin, Nett and her colleagues sought to learn everything they could about what Candida auris needs to colonize skin. The idea is that finding a way to short-circuit the skin colonization process could prevent possible infections.

The team identified potassium as essential to the growth of the fungus. Further, they constructed all kinds of mutant versions of Candida auris, with various genes deleted, and discovered that the elimination of a single gene was enough to stop the fungus from growing. The gene, called TRK1, controls a protein by the same name that transports the potassium required for Candida auris to grow and colonize skin and other surfaces.

The team recently reported its findings in the journal of the Proceedings of the National Academy of Sciences.

"We're really excited about this," says Nett. "We're very interested in the transporter because it's structurally different between cells found in animals and in Candida auris, and so we think we could potentially identify drugs that could target it and disrupt the colonization of skin."

Because fungi and animals are eukaryotes, a lot of their critical cellular machinery are similar in structure. The fact that TRK1 in Candida auris has no counterpart in animals means that potential drug candidates that target the fungus may be safe in humans, Nett says.

The team, which also includes researchers in the Department of Biochemistry and the Department of Civil and Environmental Engineering, is now investigating whether its findings extend to other fungal species.

"And we're starting to look at ways to identify inhibitors of the Trk1 protein," says Nett. "A treatment of skin colonization would be a great place to start because there currently isn't anything effective to remove Candida auris from skin."

This research was received funding from the National Institutes of Health (R01AI145939; R2AI159583).