Inhibiting C-4 Methyl Sterol Oxidase with Novel Diazaborines to Target Fungal Plant Pathogens Academic Article uri icon

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  • With resistance to current agricultural fungicides rising, a great need has emerged for new antifungals with unexploited targets. In response, we report a novel series of diazaborines with potent activity against representative fungal plant pathogens. To identify their mode of action, we selected for resistant isolates using the model fungus Saccharomyces cerevisiae. Whole-genome sequencing of independent diazaborine-resistant lineages identified a recurring mutation in ERG25, which encodes a C-4 methyl sterol oxidase required for ergosterol biosynthesis in fungi. Haploinsufficiency and allele-swap experiments provided additional genetic evidence for Erg25 as the most biologically relevant target of our diazaborines. Confirming Erg25 as putative target, sterol profiling of compound-treated yeast revealed marked accumulation of the Erg25 substrate, 4,4-dimethylzymosterol and depletion of both its immediate product, zymosterol, as well as ergosterol. Encouraged by these mechanistic insights, the potential utility of targeting Erg25 with a diazaborine was demonstrated in soybean-rust and grape-rot models of fungal plant disease.


  • Kim, Sang Hu
  • Steere, Luke
  • Zhang, Yong-Kang
  • McGregor, Cari
  • Hahne, Chris
  • Zhou, Yasheen
  • Liu, Chunliang
  • Cai, Yan
  • Zhou, Haibo
  • Chen, Xuefei
  • Puumala, Emily
  • Duncan, Dustin
  • Wright, Gerard
  • Liu, C Tony
  • Whitesell, Luke
  • Cowen, Leah E

publication date

  • June 17, 2022