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<p>Microsporidia are diverse intracellular fungal parasites of humans and agriculturally important animals. Several inhibitors have been characterized, but their microsporidian targets and the mechanisms of resistance evolution remain unknown. Using <i>C. elegans</i> and its natural microsporidian parasite <i>Nematocida parisii</i>, we serially passaged infected animals under increasing inhibitor concentrations, generating independent <i>N. parisii</i> strains resistant to albendazole or dexrazoxane. The albendazole-resistant strains all contained either heterozygous or homozygous mutations in beta-tubulin, with several strains containing beta-tubulin variants that have been observed in other albendazole-resistant organisms. Strains containing homozygous variants are resistant to several albendazole analogs, whereas the heterozygous variant-containing strains are only resistant to albendazole. Several of the albendazole-resistant strains also contain mutations in alpha-tubulin. The dexrazoxane-resistant strains all contain heterozygous mutations in topoisomerase II, and several of these mutations occur in the binding site of this inhibitor. By mapping heterozygosity of the resistant strains across the <i>N. parisii</i> genome, we observed loss of heterozygosity spanning the beta-tubulin locus in the albendazole-resistant strains containing homozygous beta-tubulin variants. Our study demonstrates the utility of forward genetics for identifying microsporidian drug targets. We also find that drug resistance arises through de novo heterozygous mutations that can subsequently become homozygous, likely via mitotic recombination.</p>

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Forward genetics reveals microsporidian drug targets and recombination-based resistance

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月3日

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  • Qingyuan Huang,
  • Xianzhi Meng,
  • Winnie Zhao,
  • Guoqing Pan,
  • Jie Chen,
  • Aaron W. Reinke

摘要

Microsporidia are diverse intracellular fungal parasites of humans and agriculturally important animals. Several inhibitors have been characterized, but their microsporidian targets and the mechanisms of resistance evolution remain unknown. Using C. elegans and its natural microsporidian parasite Nematocida parisii, we serially passaged infected animals under increasing inhibitor concentrations, generating independent N. parisii strains resistant to albendazole or dexrazoxane. The albendazole-resistant strains all contained either heterozygous or homozygous mutations in beta-tubulin, with several strains containing beta-tubulin variants that have been observed in other albendazole-resistant organisms. Strains containing homozygous variants are resistant to several albendazole analogs, whereas the heterozygous variant-containing strains are only resistant to albendazole. Several of the albendazole-resistant strains also contain mutations in alpha-tubulin. The dexrazoxane-resistant strains all contain heterozygous mutations in topoisomerase II, and several of these mutations occur in the binding site of this inhibitor. By mapping heterozygosity of the resistant strains across the N. parisii genome, we observed loss of heterozygosity spanning the beta-tubulin locus in the albendazole-resistant strains containing homozygous beta-tubulin variants. Our study demonstrates the utility of forward genetics for identifying microsporidian drug targets. We also find that drug resistance arises through de novo heterozygous mutations that can subsequently become homozygous, likely via mitotic recombination.