Genetic key to treating deadly fungal infections

Jul 24 2006

University of Minnesota researchers have discovered how a prevalent fungal pathogen that causes 10,000 deaths per year in the United States overcomes the effects of antifungal drugs by duplicating a section of one of its chromosomes.

Candida albicans, a type of yeast present in 80 percent of humans, is usually harmless. In otherwise healthy people, it can cause mild oral and vaginal infections (candiasis or thrush) that are easily treated. But in people whose immune systems are suppressed (by AIDS, chemotherapy, or drugs for surgery or organ transplantation) it can produce deadly, systemic infections, causing death in 30 to 50 percent of cases. Premature babies, whose immune systems are immature, are also at risk.

Led by Judith Berman, professor of genetics, cell biology and development, university researchers have discovered that C. albicans can neutralize an antifungal drug by modifying one of its own chromosomes. The cell duplicates one arm of chromosome 5 and deletes the other, replacing it with the duplicate arm. The altered chromosome is known as an "isochromosome." The effect of the duplication is to help the cell tolerate the antifungal drug, thus allowing the yeast to continue growing despite the presence of the drug.

The discovery, which is reported in the journal Science, could lead to strategies for making currently available antifungal drugs more effective.

"This creates important clinical opportunities," said Berman. "The next step is to find a companion drug to block the formation of isochromosomes during antifungal treatment."

Berman also explained that some cancerous tumors contain isochromosomes, which means that the finding may yield clues about how some tumors become resistant to chemotherapy and how researchers can develop companion drugs that inhibit the development of that resistance.

About 25,000 Americans develop these fungal infections each year. And in spite of treatment with antifungal drugs, 10,000 die. The number of hospital-acquired C. albicans infections is increasing. There are few drugs available to treat it and the fungus often becomes resistant to a drug, making it ineffective. The cost to the U.S. health care industry is $1 billion per year.

Berman explained that drugs that are toxic to fungi are often toxic to humans. Thus, anti-fungal drugs are usually intended to suppress, rather than kill, C. albicans. This suppression encourages the organism to evolve resistance to the drug in order to survive.