Fexinidazole results in specific effects on DNA synthesis and DNA damage in the African trypanosome

TL;DR

Fexinidazole, a new drug for African sleeping sickness, causes unique DNA damage and inhibits DNA synthesis in the parasite, offering insights into its mechanism of action.

Contribution

The study reveals distinct DNA-related effects of fexinidazole compared to other drugs, advancing understanding of its trypanocidal mechanism.

Findings

Fexinidazole uniquely inhibits DNA synthesis in African trypanosomes.

The drug causes significant DNA damage accumulation in treated parasites.

Its effects differ in timing and magnitude from other nitroaromatic drugs.

Abstract

Nitroaromatic drugs are of critical importance for the treatment of trypanosome infections in Africa and the Americas. Fexinidazole recently joined benznidazole and nifurtimox in this family when it was approved as the first oral monotherapy against Human African trypanosomiasis (HAT). Nitroaromatic prodrugs are bioactivated by the trypanosome-specific type I nitroreductase (NTR) that renders the compounds trypanocidal. The trypanocidal activity of nitroaromatic drugs has been proposed to arise from the formation of reactive oxygen species (ROS) and DNA damage. However, the specific cytotoxic effects of nitroaromatic drugs had not been thoroughly interrogated. Here we evaluate and compare the effects of clinically relevant anti-trypanosome nitroaromatic drugs using cell biology phenotypes including cell cycle progression, DNA synthesis, and DNA damage formation in the African trypanosome. We observed that fexinidazole induced cytotoxicity is distinct from related nitroaromatic drugs in its inhibition of DNA synthesis and the timing and magnitude of DNA damage formation. These findings highlight the relationship between nitroaromatic drug treatments, DNA damage formation, and ROS activation. 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.

Human African Trypanosomiasis (HAT) is a devastating parasite infection that is largely fatal if left untreated. Treatment options against HAT are limited to only a handful of drugs, most of which are heavily burdened by complex treatment regimes, host toxicity, and emerging drug resistance. Fexinidazole provides new hope in the treatment of HAT as a clinically approved oral monotherapy. However, little is known about how fexinidazole kills trypanosome parasites. Here we present the first comprehensive analysis of the trypanocidal outcomes of fexinidazole treatment. The data herein demonstrate that fexinidazole treatment causes an accumulation of DNA damage and a significant inhibition of DNA synthesis. While the precise molecular mechanisms underlying these outcomes remain to be elucidated, these findings provide critical new insights into fexinidazole’s trypanocidal activity.

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