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Duke Researchers Find Existing Drugs Can Stop Fungus That Attacks AIDS Patients

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Duke Health News 919-660-1306

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.

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