2. Academic Validation
  3. Toltrazuril inhibits Toxoplasma gondii by potentially targeting pyrimidine metabolism

Toltrazuril inhibits Toxoplasma gondii by potentially targeting pyrimidine metabolism

  • Pestic Biochem Physiol. 2025 Sep:213:106524. doi: 10.1016/j.pestbp.2025.106524.
An Yan 1,  Kai He 1,  Mingjun Xiong 1,  Xu Wang 1,  Wanxiao Jin 1,  Ruibin Wu 1,  Bolin Xia 2,  Weiwei Sun 3,  Baoliang Pan 4
Affiliations

Affiliations

  • 1 National Key Laboratory of Veterinary Public Health Security, National Animal Protozoa Laboratory and College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
  • 2 College of Wildlife and Protected Area, Northeast Forestry University, Harbin 150040, China.
  • 3 National Key Laboratory of Veterinary Public Health Security, National Animal Protozoa Laboratory and College of Veterinary Medicine, China Agricultural University, Beijing 100193, China. Electronic address: sunweiwei@cau.edu.cn.
  • 4 National Key Laboratory of Veterinary Public Health Security, National Animal Protozoa Laboratory and College of Veterinary Medicine, China Agricultural University, Beijing 100193, China. Electronic address: baoliang@cau.edu.cn.
PMID: 40744572 DOI: 10.1016/j.pestbp.2025.106524
Abstract

Toxoplasma gondii is a significant zoonotic pathogen that infects nearly all warm-blooded Animals. Available drugs for clinical treatment of toxoplasmosis are limited, creating an urgent need for development of new compounds. Toltrazuril (TOL) is a highly effective and broad-spectrum drug against parasites in Apicomplexa. In the hosts, TOL is metabolized to toltrazuril sulfone (TOLSO2) and toltrazuril sulfoxide (TOLSO), which also show potency against Apicomplexa protozoa. However, the knowledge about the effects of these metabolites on T. gondii remains unknown. The present study demonstrated that toltrazuril and its two metabolites, TOLSO and TOLSO2, markedly inhibited the invasion and proliferation of T. gondii in cells. Transmission electron microscopy revealed that these drugs substantially negatively affected the membrane structure of T. gondii. Furthermore, transcriptome and metabolome analyses indicated that toltrazuril reduces the transcription levels of dUTP pyrophosphatase (dUTPase) and thymidylate kinase (TMK), as well as the levels of dozens of metabolites, including dTMP and dUMP, potentially disrupting the stability of the pyrimidine network. More importantly, animal experiments have demonstrated that toltrazuril can completely protect mice against T. gondii Infection. Taken together, the present findings demonstrate toltrazuril is a promising therapeutic candidate for toxoplasmosis.

Keywords

Pyrimidine metabolism; Thymidylate kinase; Toltrazuril; Toxoplasma gondii; dUTPase.

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