March 16, 2009

Thwarting Fungal Defenses

Microscope image of a fungus Aspergillus fumigatus up close. Centers for Disease Control and Prevention.

Researchers have devised a way to stymie fungi's ability to become resistant to antifungal drugs. The advance paves the way for future therapies to treat fungal infections, a leading cause of death for people with weakened immune systems.

Fungi are a sort of primitive plant, and they live all around us. They include mushrooms, mold and mildew. Athlete's foot and yeast infections are the most common types of fungal infection, but fungi can also cause lung and other serious infections. These can be deadly for people with weakened immune systems, including patients with HIV and those undergoing chemotherapy, major surgery or transplantation.

Treating fungal infections can be extremely difficult. Few drugs are available, and fungi become resistant to them. A team led by Dr. Susan Lindquist and Dr. Luke Whitesell at the Massachusetts Institute of Technology and Dr. Leah E. Cowen at the University of Toronto previously established that a protein called Hsp90 helps a diverse range of fungi become resistant to antifungal drugs. Hsp90 plays a number of roles in the fungal cell, one of which is to help the cells respond to stress.

In the current study, the team tested whether Hsp90 inhibitors could help fight fungal infections. Their work, published in the February 24, 2009, issue of Proceedings of the National Academy of Sciences, was funded by NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and several other organizations.

For a model system, the team began with the larvae of the greater wax moth Galleria mellonella. Past studies have found it to be an inexpensive and practical way to evaluate antifungal drugs. The researchers found that, by combining Hsp90 inhibitors known to be well tolerated in humans with common antifungal drugs, they could rescue larvae from infection by 2 important fungi—Candida albicans, a common cause of hospital-acquired infectious disease, and Aspergillus fumigatus, the most deadly mold known, with mortality rates up to 90%.

Mice with fungal infections didn’t tolerate the Hsp90 inhibitors well, so the researchers had to devise another way to confirm that inhibiting Hsp90 could boost the effectiveness of an antifungal drug. They genetically engineered C. albicans to disable their ability to ramp up Hsp90 production. The common antifungal drugs proved much more effective when the mice were infected with the genetically modified fungi.

These results establish Hsp90 as a potential target for the development of combination therapies against fungal disease. However, the difficulties in mice highlight the potential challenges in developing Hsp90 inhibitors for use in the clinic. Hsp90 is an important protein in organisms from fungi to humans and has been conserved over time. Fungal-specific Hsp90 inhibitors haven’t yet been identified.

Several Hsp90 inhibitors are currently in clinical or late-stage preclinical testing for anti-cancer activity. In fact, extensive compound collections have already been generated in the search for anticancer Hsp90 inhibitors, providing a resource for identifying fungal-specific inhibitors. Potential targets include proteins that interact with Hsp90, which vary more than Hsp90 itself. In preliminary work, the researchers say they’ve successfully identified compounds that affect the Hsp90 pathway in yeast but not mammalian cells.

—by Harrison Wein, Ph.D.

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