New Antifungal Drug Fights Fungi in Mice Without Toxicity

By applying a unique molecular "scaffold," researchers have created a broad-spectrum antifungal drug that homes in on a key fungal compound without disrupting the host's cholesterol – a frequent side effect of current therapies. The compound's selectivity could help avoid the toxic side effects that have plagued antifungal therapy regimens and frustrated clinicians for decades. To deal with fungal infections, clinicians often turn to a drug called amphotericin B, which is considered the gold-standard for a wide range of different fungal pathogens. The drug has reigned supreme for more than 50 years, but it comes with dangerous side effects such as kidney and blood toxicity. These side effects arise because the drug targets a fungal compound called ergosterol, which shares many structural features with mammalian cholesterol. As a result, amphotericin B frequently disrupts cholesterol biology, constraining its clinical utility. To uncouple ergosterol and cholesterol, Wei Liu and colleagues engineered a new antifungal named mandimycin M16, which they built on a molecular framework they called a 5 +1 polyene scaffold. The scaffold design enables the drug to more specifically target fungal ergosterol through the C5-C8 diene system, which is absent in cholesterol. M16 neutralized 11 priority threat fungal pathogens in vitro – including multidrug-resistant strains – without binding to cholesterol. It also outperformed amphotericin B in several mouse models of systemic Candida infections without causing kidney injury. "M16 provides a mechanistic and structural foundation for designing next-generation antifungal drugs […] offering a pathway toward antifungal agents that address the therapeutic gaps left by current treatments," Liu et al. write.