New Target for Leishmaniasis Treatment Identified

University of Kansas researchers have made a significant advancement in understanding how Leishmania parasites, responsible for leishmaniasis, synthesize ergosterol, a crucial component of their cell membranes. This discovery, published in Nature Communications, could lead to more effective treatments for visceral leishmaniasis (VL), a disease affecting approximately 1 million people worldwide and causing about 30,000 deaths annually.

The study, led by Michael Zhuo Wang, resolves a long-standing mystery in the field. For decades, scientists have been puzzled by the ineffectiveness of azole antifungal drugs against leishmaniasis, despite the parasites' similarity to fungi in their use of ergosterol.

Wang and his team found that Leishmania parasites use a different enzyme, CYP5122A1, for ergosterol biosynthesis. This enzyme works alongside the traditional CYP51 pathway targeted by antifungal azoles. "So those azoles don't work very well against leishmania unless you have an azole that also inhibits the new pathway, the CYP5122A1," Wang explained. "Then, all of a sudden, they're much more active against leishmania."

The research team demonstrated that the CYP5122A1 gene encodes an essential sterol C4-methyl oxidase in the Leishmania parasite through extensive biochemical characterization. This finding clarifies the enzyme's role in the ergosterol biosynthesis pathway and provides a new target for drug development.

Wang suggests that pharmaceutical companies should focus on developing therapies that target CYP5122A1. "This tells us how we should repurpose these existing antifungal azoles through screening against this new target," he said. "The ones that actually inhibit this new target should have a better chance to work against leishmania infection."