Human skin, hair and nails are all at risk of fungal infections. Although these infections are often not serious, they’re difficult to resolve completely and sometimes recur after treatment — sometimes for years. They are also often proof against treatment, including a standard class of antifungals called azoles.
A study published this week points to a recent approach to increase the effectiveness of azoles in treating these infections — combining them with commonly available drugs called bisphosphonates, that are commonly utilized in osteoporosis. are used for treatment. Previous work by the identical research group has shown that adding bisphosphonates to azoles can effectively treat yeast infections and species. The recent study extends this finding to dermatophytes, which cause superficial infections.
The study showed that bisphosphonates could possibly be repurposed to be used with azole antifungals, that are relatively nontoxic, and that the mix could possibly be easily tested in clinical studies.
“There aren't many good antifungal drugs around, and fungi will always develop resistance no matter how you treat them,” said senior writer Dee Carter, a pathologist on the University of New South Wales in Australia. “What we're recommending, to use the 2 drugs at the same time, is that the likelihood of resistance is very low.”
Carter says she was slightly surprised to see the synergistic effect in dermatophytes. The research project began years ago, she says, when her group conducted a series of genomic analyzes on the response of pathogenic yeast to drug treatment. This study led them to a genetic pathway that’s “upstream” of the pathway targeted by the azoles, and is as an alternative targeted by the bisphosphonates. “It's often a good way to make drugs work, to target processes that are interconnected,” Carter said.
In the lab, Carter and his team tested 3 commonly available bisphosphonates (risedronate, alendronate, and zoledronate) together with 3 commonly available azole antifungals (fluconazole, itraconazole, and ketoconazole). They tested them against clinical isolates from a various range of dermatophyte species that cause superficial infections. The combination of zoledronate and ketoconazole was particularly effective against 8 out of 9 species tested. It also prevented the event of resistance.
Aidan Kane, mycologist, lead writer of the study and Ph.D. student in Carter's lab used fluorescence microscopy and other methods to indicate that the drug combination weakened the cell membrane a lot that the fungus couldn’t survive. In addition to dermatophytes, the group also found that bisphosphonate-azole mixtures can act against molds that cause invasive disease, suggesting one other potential clinical application for the drugs.
“You can use these compounds directly for superficial infections, like or dermatophyte infections, and we're hoping that with modified forms of the drug we can create something that's systemic as well,” Carter said. Work,” Carter said. “The next step is to proceed testing the bisphosphonate-azole combination in animal models, after which test it in clinical trials.”