Analysis of New Anti-Parasite Drug May Help Advance Treatments

Trypanosomatids are parasites that can result in over one billion potentially fatal infections per year globally. In Africa, Human African Trypanosomiasis (HAT), better known as Sleeping Sickness, causes a devastating infection that without treatment results in death.

Unfortunately, most drug therapies against HAT have mixed results and multiple adverse side effects. The newest drug to offer hope, fexinidazole, is the first oral monotherapy against HAT. Yet, the mechanism of fexinidazole parasite killing was unknown.

Now, a research team led by Stony Brook University scientists has conducted the first comprehensive analysis of how fexinidazole kills trypanosomatid parasites.

The results of their analysis, recently published in the journal PLOS Neglected Tropical Diseases, contributes a critical new understanding of fexinidazole's mechanism of action and insights to how parasites build up resistance to the drug - essential steps in advancing effective treatments for HAT.

Lead author Galadriel Hovel-Miner, associate professor in the Department of Microbiology and Immunology in the Renaissance School of Medicine (RSOM) at Stony Brook University, and colleagues used cutting-edge cell biology methods to demonstrate that fexinidazole causes DNA damage in the HAT parasites, which leads to their death. The Hovel-Miner Lab also applies novel genetics approaches to identify biological pathways associated with drug mechanisms of action and anti-parasite drug resistance. They are now applying this approach to deepen the understanding of anti-parasitic drug mechanisms.

HAT, or Sleeping Sickness, is caused by protozoan parasites transmitted by infected tsetse flies. Broadly, kinetoplastida parasites include the African trypanosomes (Trypanosoma brucei), Leishmania species, and the American trypanosome (Trypanosoma cruzi). The diagnosis and treatment for HAT are complex.

American trypanosome infections result in Chagas disease, a chronic infection that causes heart failure in 20 to 30 percent of patients. Previously, the disease was isolated to South America and Central America. As of September 2025, the Centers for Disease Control and Prevention (CDC) reported that Chagas Disease is emerging as an endemic infection in the Southern United States.

Research Findings

In the PLOS Neglected Tropical Diseases paper, the research team analyzed three nitroaromatic drugs designed to kill parasites, two previous drugs and the newer fexinidazole. They demonstrated that fexinidazole treatment causes an accumulation of DNA damage and a significant inhibition of DNA synthesis. The results highlight the cytotoxic effects of fexinidazole for the first time since the start of its use in sub-Saharan Africa in 2019.

The authors say the findings also highlight the relationship between nitroaromatic drug treatments, DNA damage formation, and the ROS (reactive oxygen species) activation, a process essential for parasitic cell proliferation.

"We found that the nuclei are aberrant in the parasites because the drug causes DNA damage, and that is the essential action that leads to death of these parasites," Hovel-Miner said. "While the precise molecular mechanisms underlying these outcomes remain to be elucidated, our findings provide critical new insights to fexinidazole's trypanocidal activity."

Hovel-Miner explained that while the infectious diseases caused by each Trypanosomatid parasite are diverse in pathology and global distribution, their core biology, genomics and metabolism are broadly shared. Thus, establishing mechanistic understanding of fexinidazole and related drugs will uncover improved therapeutics in the future.

Additionally, the paper in PLOS NTD highlights how "deconvolving the relationship between anti-parasitic drugs and the molecular basis of their cytotoxic outcomes will support future mechanistic understanding and enable improved drug design."

Parasite Infections on the Rise in the United States

Because Chagas disease, or American Trypanosomiasis, is an emerging infection in the southern part of the U.S., and now endemic in the region, the need for better treatments is even more important.

"Two of the drugs that we analyzed in this paper, nifurtimox and benznidazole, are the only drugs available for Chagas disease, and they can be toxic and have poor treatment outcomes," Hovel-Miner said. "Therefore, fexinidazole or related drugs that kill parasites via DNA damage could prove very important as American trypanosomiasis spreads in the United States."

The CDC indicates that Chagas disease is prevalent in 21 nations in the Americas, which now includes the U.S., largely because of climate change as warmer temperatures are favorable parasitic infections. Hovel-Miner's research team and collaborators will continue to focus on identifying novel genes, pathways and cell biology phenotypes associated with anti-trypanosome therapeutics.

Discoveries emerging from the Hovel-Miner Lab's novel genetic approaches are establishing a link between mitochondrial stress and drug resistance that will identify novel targets for future drug development.

The Hovel-Miner Lab received National Institutes of Health (NIH) funding of more than $500,000 in 2025, and an expected $300,000 plus anticipated for 2026 and 2027.