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<p><i>Toxoplasma gondii</i> stands among nature’s most successful eukaryotic pathogens, a status achieved through refined mechanisms for intracellular survival that enable pan-vertebrate host tropism. This ecological dominance derives principally from evolutionary refinements in metabolic plasticity, a modular integration of <i>de novo</i> biosynthesis with high-efficiency nutrient scavenging systems. The pyrimidine biosynthesis pathway is indispensable for robust parasite proliferation. Our previous work demonstrated that exogenous uracil supplementation bypasses the <i>DHO</i> deficiency-induced growth restriction. Here, we reconfirm the functional pyrimidine rescue using an <i>ATC</i>-knockout parasite line, identifying a protective salvage route that maintains pyrimidine pool homeostasis. Pharmacological suppression of <i>T. gondii</i> growth with NBMPR, a potent hENT1 antagonist, confirms that host hENT1 serves as a critical conduit for pyrimidine and purine acquisition by the parasite. Evolutionary analysis identifies <i>Tg</i>ENT1, <i>Tg</i>ENT3, TGGT1_359630, and <i>Tg</i>AT1 as hENT1 homologs, with <i>Tg</i>ENT1 demonstrating the strongest phylogenetic clustering with hENT1. The computational models predict interactions between <i>Tg</i>ENT1 and a spectrum of ligands (NBMPR, nucleosides, and nucleobases), supporting its classification as a broad-specificity nucleoside/nucleobase transporter, consistent with the function of hENT1. The genetic intractability of <i>Tg</i>ENT1, however, indicates that it likely plays an essential role in parasite proliferation. Our study reveals that NBMPR-mediated inhibition of both <i>Tg</i>ENT1 and hENT1 disrupts a hierarchical transport cascade essential for <i>T. gondii</i> to acquire pyrimidines and purines from the host, highlighting the promise of a strategy that simultaneously targets both parasite and host nutrient acquisition pathways for improved anti-toxoplasmosis therapy.</p>

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Anti-Toxoplasma activity of NBMPR is mediated through the inhibition of nucleoside and nucleobase transporters

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月16日

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  • Ming Pan,
  • Shu-Qin Tang,
  • Ceng-Ceng Ge,
  • Shi-Jie Fan,
  • He-Xin He,
  • Man-Man Bian,
  • Bang Shen,
  • Si-Yang Huang

摘要

Toxoplasma gondii stands among nature’s most successful eukaryotic pathogens, a status achieved through refined mechanisms for intracellular survival that enable pan-vertebrate host tropism. This ecological dominance derives principally from evolutionary refinements in metabolic plasticity, a modular integration of de novo biosynthesis with high-efficiency nutrient scavenging systems. The pyrimidine biosynthesis pathway is indispensable for robust parasite proliferation. Our previous work demonstrated that exogenous uracil supplementation bypasses the DHO deficiency-induced growth restriction. Here, we reconfirm the functional pyrimidine rescue using an ATC-knockout parasite line, identifying a protective salvage route that maintains pyrimidine pool homeostasis. Pharmacological suppression of T. gondii growth with NBMPR, a potent hENT1 antagonist, confirms that host hENT1 serves as a critical conduit for pyrimidine and purine acquisition by the parasite. Evolutionary analysis identifies TgENT1, TgENT3, TGGT1_359630, and TgAT1 as hENT1 homologs, with TgENT1 demonstrating the strongest phylogenetic clustering with hENT1. The computational models predict interactions between TgENT1 and a spectrum of ligands (NBMPR, nucleosides, and nucleobases), supporting its classification as a broad-specificity nucleoside/nucleobase transporter, consistent with the function of hENT1. The genetic intractability of TgENT1, however, indicates that it likely plays an essential role in parasite proliferation. Our study reveals that NBMPR-mediated inhibition of both TgENT1 and hENT1 disrupts a hierarchical transport cascade essential for T. gondii to acquire pyrimidines and purines from the host, highlighting the promise of a strategy that simultaneously targets both parasite and host nutrient acquisition pathways for improved anti-toxoplasmosis therapy.