Researchers at the Medical Center may have a better understanding of the way antifungal drugs kill their targets, based on a study of patients taking immune system-suppressing drugs after transplants.
"From a biotech standpoint, these findings clearly lead the way to the development of new antifungal drugs or drugs that can be used in combination [with those already available]," said Dr. Ted White, associate professor at the University of Washington.
"From the academic side, this is an extremely useful tool for understanding how drugs interact with fungi and the more we know about that relationship, the better we are at treating them," he said.
Researchers specifically studied azoles, the most common antifungal drugs, used because they are orally active and nontoxic to humans. Administered alone, azoles do not kill fungal cells, but rather inhibit their growth.
Because fungal populations are not killed, they often become resistant to antifungal drugs.
But researchers found that when azoles were used in combination with immune-suppressing drugs, they were particularly effective in killing fungal infections.
Scientists believe the effectiveness of the combinations may be related to calcineurin, an enzyme crucial in activating immune cells.
"It appears that fungal cells have critical calcium centers that require calcineurin in order for their membranes to survive under stress," said lead researcher Dr. Joseph Heitman, associate professor of genetics and director of Duke's Center of Microbial Pathogenesis.
Heitman, whose work was published in last month's issue of the European Molecular Biology Organization Journal, explained that calcineurin is blocked by immune-suppressing drugs, which cripples the fungal cells' stress response and allows the azoles to kill them.
This finding discounts previous proposals that these drugs worked by inhibiting a pump that normally prevents azoles from entering the cell, giving scientists a much better understanding of the mechanism by which antifungal drugs work.
Researchers conducted their study on patients who underwent organ or bone marrow transplants, who are typically treated with immunosuppressant drugs like cyclosporin and FK506 to block the body's natural rejection of transplanted organs.
Although non-clinical trials have shown promise, researchers will continue to learn more about drug combinations and their mechanisms.
"There are only a limited number of antifungal drugs and since azoles are already so widely used, if you could combine them with some other drugs, it increases the likelihood that [they] could be extremely effective in treating fungal infections," Heitman said.
"We also need to identify other steps of the [fungal] biosynthetic pathway that become incredibly synergistic when combined with calcineurin pathways."
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