One Health drug discovery for animal trypanosomiasis: expanding the focus from efficacy to environmental safety

Subtitle:expanding the focus from efficacy to environmental safety

Abstract:Animal trypanosomiasis (AT) is a vector-borne parasitic disease caused by multiple Trypanosoma species, including T. congolense, T. vivax, T. brucei brucei, T. b. evansi, and T. b. equiperdum. Affecting livestock across Africa, Asia, and Latin America, AT undermines food security, rural development, and economic stability in endemic regions. Despite its vast socioeconomic burden, the disease remains critically neglected, with limited investment in drug development. Treatment still relies on a small arsenal of decades-old trypanocides, which suffer from toxicity, limited efficacy, and rising drug resistance. Given the lack of prophylactic vaccines and the emergence of resistant strains, novel, safe, and broad-spectrum therapeutics are urgently needed. This thesis aimed to (i) evaluate and characterize novel antitrypanosomal compounds with efficacy across multiple Trypanosoma species, and (ii) implement a One Health drug discovery framework that integrates early safety and environmental profiling. Nucleoside analogues were chosen as the chemical class of interest, leveraging the purine auxotrophy of African trypanosomes and the success of nucleoside-based drugs in oncology, virology, and parasitology. Among the tested candidates, two compounds emerged as promising leads. 3′-Deoxytubercidin, a 7-deazaadenosine analogue with potent activity against both stages of HAT, achieved sterile cure in murine models of Surra (T. b. evansi) and Dourine (T. b. equiperdum). It was also evaluated with preliminary ecotoxicity tests using Daphnia magna and Desmodesmus subspicatus, indicating a relatively low environmental risk profile. However, this compound did not undergo mechanistic or genotoxicity assessments within the scope of this thesis. The second lead, 6-thiophenyl 7-deazapurine riboside analogue (FH15967/compound 3), showed submicromolar in vitro activity against major AT-causing species, including T. vivax. The compound demonstrated excellent metabolic stability and successfully cured multiple AT infections in mouse models. Mechanistic studies identified the parasite’s adenosine kinase (ADKIN) as essential for drug activation and suggested P1-type nucleoside transporters as primary uptake routes. Comparative metabolomic profiling further supported intracellular phosphorylation as a prerequisite for activity. In addition to efficacy and mode-of-action, FH15967 underwent early safety evaluations, including three in vitro genotoxicity assays (Vitotox, micronucleus, and Comet), all confirming a lack of DNA-damaging potential. Ecotoxicological testing of FH15967 showed no significant toxicity to aquatic indicator species, supporting alignment with One Health sustainability goals. In summary, this thesis advances nucleoside analogues as a promising therapeutic class for treating AT. Through systematic evaluation of their efficacy, safety, and environmental impact, the research provides a strong foundation for continued development aligned with One Health principles.

Publication year:2025

Keywords:Biology

Accessibility:Open