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<p>Shared enzymatic targets between azoles used in agriculture as fungicides and clinical antifungals are hypothesized to have led to the drift of resistant fungal isolates from field to clinic, reducing efficacy of azoles in infectious disease treatment. Recent discovery of a novel herbicide, tetflupyrolimet, and a potential clinical antifungal, olorofim, both targeting dihydroorotate dehydrogenase (DHODH), raises concern that widespread use of tetflupyrolimet may similarly cause clinical resistance to olorofim in <i>Aspergillus</i> isolates migrating from agricultural settings. Using minimum inhibitory concentration analysis on <i>Aspergillus</i> subspecies, enzymatic assays of recombinant DHODH, and a series of <i>DHODH</i> knockout yeast strains complemented with various <i>DHODH</i> orthologs, we demonstrate that tetflupyrolimet is highly selective for plant DHODH over <i>Aspergillus</i> DHODH. Based on the inability of tetflupyrolimet to inhibit <i>Aspergillus</i> DHODH or hinder growth of various <i>Aspergillus</i> species, the data demonstrate that risk of olorofim resistance developing in <i>Aspergillus</i> due to agrochemical use of the herbicide tetflupyrolimet is minimal.</p>

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Tetflupyrolimet shows selectivity for plant dihydroorotate dehydrogenase over Aspergillus orthologs

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月17日

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  • Sang-Ic Kim,
  • Venkataphanikanth Turlapati,
  • Bhavna Agashe,
  • Qun Lu,
  • Sriram Satagopan,
  • James A. Sweigard,
  • Ryan P. Emptage

摘要

Shared enzymatic targets between azoles used in agriculture as fungicides and clinical antifungals are hypothesized to have led to the drift of resistant fungal isolates from field to clinic, reducing efficacy of azoles in infectious disease treatment. Recent discovery of a novel herbicide, tetflupyrolimet, and a potential clinical antifungal, olorofim, both targeting dihydroorotate dehydrogenase (DHODH), raises concern that widespread use of tetflupyrolimet may similarly cause clinical resistance to olorofim in Aspergillus isolates migrating from agricultural settings. Using minimum inhibitory concentration analysis on Aspergillus subspecies, enzymatic assays of recombinant DHODH, and a series of DHODH knockout yeast strains complemented with various DHODH orthologs, we demonstrate that tetflupyrolimet is highly selective for plant DHODH over Aspergillus DHODH. Based on the inability of tetflupyrolimet to inhibit Aspergillus DHODH or hinder growth of various Aspergillus species, the data demonstrate that risk of olorofim resistance developing in Aspergillus due to agrochemical use of the herbicide tetflupyrolimet is minimal.