Doc Summary
A breakthrough in understanding How a single-cell parasite makes ergosterol (its version of cholesterol) could lead to more effective drugs for human leishmaniasis, a parasitic disease that afflicts about 1 million people and kills about 30,000 people around the world every year.
The findings, reported in Nature Communications, also solve a decades-long scientific puzzle that’s prevented drugmakers from successfully using azole antifungal drugs to treat visceral leishmaniasis, or VL.
About 30 years ago, scientists discovered the two species of single-cell parasites that cause VL, Leishmania donovani and Leishmania infantum, made the same lipid sterol, called ergosterol, as fungi proven susceptible to azoles antifungals. These azoles antifungals target a crucial enzyme for sterol biosynthesis, called CYP51.
While not fungi, both Leishmania species have biochemical similarities to fungi in their plasma membrane, where ergosterol helps maintain cellular integrity and supports a host of biological functions, much as cholesterol does in humans.
“People looked into the sterol profile of the parasites and discovered they primarily have ergosterol,” said study corresponding author Michael Zhuo Wang, professor of pharmaceutical chemistry at the University of Kansas School of Pharmacy. “This sterol is the main component of their plasma-membrane sterols. A similar case can be observed in fungi. Fungal organisms also have a high amount of ergosterol in their membranes. There was an original instinct to use antifungal azoles to try to block that pathway.”
However, scientists were unable to effectively use antifungals against VL.
“In the research lab and some of the clinical trials, some azoles worked a little bit, and some other azoles didn’t work at all,” Wang said. “I eventually focused on this sterol pathway a scientific question — if this parasite also uses ergosterol, you’d think all the antifungal azoles would work against this parasite.”
Along these lines, Wang started his independent research career as part of a group at the University of North Carolina-Chapel Hill called the Consortium for Parasitic Drug Development.
“We were interested in developing New drugs against neglected tropical diseases,” he said. “One of these diseases is leishmaniasis. The other one is the African sleeping sickness. Leishmaniasis, spread by a sandfly vector in warmer climates, can cause really devastating infection of internal organs such as the liver and the spleen, as well as the bone marrow.”
In his New scholarly paper, Wang and his collaborators have largely solved that longstanding scientific question. They show the parasites that cause leishmaniasis are vulnerable via a different pathway for biosynthesis of their ergosterol, known as the CYP5122A1 enzyme. Therefore, azole antifungals targeting the CYP5122A1 enzyme as well as the traditional CYP51 pathway should be much more effective at treating leishmaniasis.
