DURHAM, N.C. -- Researchers at Duke University Medical Center have discovered that an existing class of drugs used to treat organ transplant recipients may also help fight a type of fungus that infects and often kills AIDS patients and other people with weakened immune systems.
The researchers said the compounds effectively stopped growth of the fungus in test tube studies. They are now testing the most promising compound in animals afflicted with fungal infections.
In the May 15 issue of the EMBO Journal, geneticist Dr. Joseph Heitman, a Howard Hughes Medical Institute investigator; fungus expert Dr. John Perfect of the division of infectious diseases; and their colleagues identified a trait in the fungus Cryptococcus neoformans that allows it to infect people, and suggested a potential new drug target to stop the infection.
The studies were funded by the Veterans Administration Research Center on AIDS and HIV infection and a U.S. Public Health Service grant.
C. neoformans is the leading cause of fungal meningitis, a serious and sometimes deadly infection of the thin membrane that covers and protects the brain. The fungus enters the body through the lungs when a person breathes in its airborne spores. In a healthy person, it is mostly harmless, because the immune system effectively combats the organism. However, in people with suppressed immune systems, the organism can evade the host defense and infect the brain.
Between 6 percent and 10 percent of AIDS patients develop this life-threatening infection, the researchers said. In about 40 percent of these patients, it is the first infection they develop when their infection progresses to AIDS.
"There is a pressing need for new anti-fungal agents against Cryptococcus and other fungi because we are identifying an increase both in the number of cases of serious fungal infection and in strains of fungus resistant to current treatments," Perfect said. "Ironically, our successes with antibiotics have helped foster this increase. Patients are surviving bacterial infections only to then develop fungal infections. Our finding may be another step in developing an effective line of defense against these potentially deadly pathogens."
Once an infection is established, treatment options are limited. The most effective anti-fungal drug, called fluconazole, requires lifetime therapy in AIDS patients and has side effects such as nausea and kidney disease.
The researchers found the immunosuppressive drugs cyclosporin and FK506, which are used to treat organ transplant recipients, prevent C. neoformans from growing at body temperature, but not at room temperature.
In addition to Heitman, who is an assistant professor of genetics and pharmacology, and Perfect, the research team included Audrey Odom, Scott Muir, Eric Lim and Dena Toffaletti.
Their findings build on an earlier paper, published in the January 1997 issue of Antimicrobial Agents and Chemotherapy, in which Odom, Maurizio del Poeta, Perfect and Heitman showed a non- immunosuppressive drug in the same family as cyclosporin and FK506 also blocks the fungus from growing at body temperature.
"It is difficult to find effective treatments for fungal infections because fungi, unlike bacteria, use the same basic machinery as humans to carry out life processes," Heitman said. "This means there are very few drug targets for fungi. We believe we have found one such target."
In previous research, Heitman showed cyclosporin and FK506, two leading anti-organ rejection drugs, both jam the mechanism that activates immune system cells by blocking a single target inside cells, a protein called calcineurin.
Since the drugs only work at body temperature, calcineurin must be required for cells to grow at this temperature, Heitman said. To test the idea, the researchers disrupted the gene for calcineurin in the fungus. They found that the mutant fungus lacking calcineurin could no longer survive at body temperature, and as a consequence, could no longer infect animals. They also found calcineurin is required for fungal growth at two other conditions found in animals and people: a high pH and high carbon dioxide environment.
"This finding indicates that calcineurin is required for virulence," Heitman said.
Since pharmaceutical researchers have tested many calcineurin inhibitors as treatments to prevent organ transplant rejection, Heitman tried several that had been rejected as organ transplant drugs because they did not suppress the immune system. One of these, a compound called
L-685,818, a close analog of the U.S. Food and Drug Administration-approved drug FK506, proved toxic to the fungus, while sparing normal immune system function. The Duke researchers are now testing the compound, produced by the pharmaceutical company Merck, in animals infected with the fungus.
"Ironically, calcineurin can both suppress the immune system and kill the fungus," Perfect said. "Thus development of specific inhibitors that kill the fungus and not harm people will be necessary. That now appears possible."