"Fungal infections are a significant cause of morbidity and mortality worldwide and current antifungal drugs have drawbacks. These new drugs may pave the way for the development of a new class of antifungals," said principal investigator Maurizio Del Poeta, MD, a professor in the Department of Molecular Genetics and Microbiology at Stony Brook University, Stony Brook, New York.
Fungal infections are most commonly found in individuals with medical conditions that compromise the immune system, such as AIDS, or individuals who are being treated with immunosuppressives, such as those battling cancer. The three classes of antifungal drugs currently available--azoles, polyenes, and echinocandins--are far from optimal.
"Even with treatment, the mortality rate of invasive fungal infections is over 50%," said Dr. Del Poeta. "The drugs don't work that well. They are toxic, so they affect other organs, and they are static, meaning they may be able to stop a fungus from replicating but they are not able to kill the fungus." Current antifungals also have a narrow spectrum of activity, and some interact with other drugs such as chemotherapy agents and immunosuppressants."
Previous research has shown that when fungal cells lack a lipid called glucosylceramide (GlcCer), they are unable to replicate. Seeking to exploit this weakness and develop a new class of antifungals, an international group of researchers screened a synthetic drug library for compounds that target the synthesis of fungal but not mammalian GlcCer. "The enzymes that are important for the synthesis of fungal glucosylceramide are different than the ones important for the synthesis of mammalian glucosylceramide," said Dr. Del Poeta. "We thought that because the pathway is totally different, we could specifically target the fungal glucosylceramide without affecting mammalian glucosylceramide, and that is exactly what we did."
They identified two compounds, BHBM and its derivative DO, that decreased levels of fungal but not mammalian glucosylceramide. In test tube and animal studies, these compounds were highly effective against several pathogenic fungi and were well tolerated in animals. The drugs were effective when used alone or in combination with other classes of antifungals. The researchers plan to spend the next five years fine-tuning their research and identifying even more effective compounds that inhibit fungal glucosylceramide.
Serious fungal infections cause 1.3 million deaths annually worldwide. The most common and life-threatening fungal infections are cryptococcosis, candidiasis, aspergillosis, and pneumocystosis.