A research team led by Stony Brook University has conducted the first comprehensive analysis of how the drug fexinidazole kills trypanosomatid parasites, which are responsible for more than a billion potentially fatal infections globally each year. The findings, published in PLOS Neglected Tropical Diseases, provide important insights into the drug's mechanism of action and how resistance may develop.
Trypanosomatids cause diseases such as Human African Trypanosomiasis (HAT), also known as Sleeping Sickness, which is transmitted by tsetse flies in Africa. Without treatment, HAT is usually fatal. Fexinidazole is currently the only oral monotherapy available for HAT, but its method of killing parasites had not been fully understood until now.
The study was led by Galadriel Hovel-Miner, PhD, Associate Professor at Stony Brook University's Renaissance School of Medicine. Using advanced cell biology techniques, Dr. Hovel-Miner and her colleagues demonstrated that fexinidazole causes DNA damage in trypanosomatid parasites, leading to their death.
“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,” said Dr. Hovel-Miner. “While the precise molecular mechanisms underlying these outcomes remain to be elucidated, our findings provide critical new insights to fexinidazole’s trypanocidal activity.”
The researchers also analyzed two older nitroaromatic drugs—nifurtimox and benznidazole—alongside fexinidazole. They showed that all three drugs result in DNA damage and inhibit DNA synthesis within parasite cells. The study highlights a link between nitroaromatic treatments and reactive oxygen species (ROS) activation—a process crucial for parasite proliferation.
Dr. Hovel-Miner noted that understanding these mechanisms could inform improved therapies for both African and American forms of trypanosome infections since their core biology shares similarities.
“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,” Dr. Hovel-Miner explained. “Therefore, fexinidazole or related drugs that kill parasites via DNA damage could prove very important as American trypanosomiasis spreads in the United States.”
Chagas disease—which is caused by Trypanosoma cruzi—is now considered endemic in parts of the southern United States according to recent reports from health authorities such as the CDC. Climate change has contributed to this trend by creating warmer conditions favorable for parasitic infections across 21 nations in the Americas.
The research team will continue studying genes and pathways linked with anti-trypanosome therapeutics using novel genetic approaches developed at Stony Brook University. Their work aims to uncover targets for future drug development by establishing connections between mitochondrial stress responses and resistance mechanisms.
Funding for this research includes more than $500,000 awarded by the National Institutes of Health (NIH) in 2025 with additional anticipated support through 2027.