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<p>The parasite <i>Cryptosporidium</i> is a leading cause of life-threatening diarrhoeal disease, and effective treatment is not available. Clofazimine, an antimicrobial used for treatment of leprosy and tuberculosis, was found to have potent anti-<i>Cryptosporidium</i> activity but it failed in a human trial. This was attributed to poor bioavailability. Here we observed differential clofazimine susceptibility among <i>C. parvum</i> parasite isolates, which we exploit to identify a single genomic locus encoding the type II NADH dehydrogenase (NDH2) in an unbiased genetic cross. Targeted genetic ablation of <i>ndh2</i> resulted in high-level clofazimine resistance and biochemical studies demonstrated NDH2-mediated electron transfer to clofazimine. Through genomic analyses, we uncovered heterogeneity at the <i>ndh2</i> locus for <i>C. parvum</i> and <i>C. hominis</i>, and widespread carriage of a conserved attenuated allele across multiple continents. This heterogeneity allows parasites genomically linked through frequent sexual recombination to adjust to changing NDH2 requirements and predisposes <i>Cryptosporidium</i> to evade clofazimine treatment.</p>

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Genomic heterogeneity of NAD(P)H dehydrogenase predisposes Cryptosporidium to clofazimine resistance

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月13日

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  • Gracyn Y. Buenconsejo,
  • Sebastian Shaw,
  • Rui Xiao,
  • Aurélia C. Balestra,
  • Keenan M. O’Dea,
  • Peng Jiang,
  • Bingjie Xu,
  • Dongqiang Wang,
  • Guan Zhu,
  • Daniel P. Beiting,
  • Boris Striepen

摘要

The parasite Cryptosporidium is a leading cause of life-threatening diarrhoeal disease, and effective treatment is not available. Clofazimine, an antimicrobial used for treatment of leprosy and tuberculosis, was found to have potent anti-Cryptosporidium activity but it failed in a human trial. This was attributed to poor bioavailability. Here we observed differential clofazimine susceptibility among C. parvum parasite isolates, which we exploit to identify a single genomic locus encoding the type II NADH dehydrogenase (NDH2) in an unbiased genetic cross. Targeted genetic ablation of ndh2 resulted in high-level clofazimine resistance and biochemical studies demonstrated NDH2-mediated electron transfer to clofazimine. Through genomic analyses, we uncovered heterogeneity at the ndh2 locus for C. parvum and C. hominis, and widespread carriage of a conserved attenuated allele across multiple continents. This heterogeneity allows parasites genomically linked through frequent sexual recombination to adjust to changing NDH2 requirements and predisposes Cryptosporidium to evade clofazimine treatment.