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<p>The rise of drug resistance and limitations of current antifungal treatments highlight the urgent need for innovative antifungal strategies. Here we present the development of <i>cis</i>-fumaramidmycin-derived analogs inhibiting the interactions of ribosome assembly factor Mrt4 with rRNA to combat fungal infections. Through antifungal screening, we identified a promising lead <b>20</b> with strong efficacy against various drug-resistant fungi, including notorious super-fungus <i>Candida auris</i>. A comprehensive approach combining active-and-inactive-based protein profiling (AIBPP), chemical-genetic profiling, and fluorescence polarization revealed that the antifungal activity of <b>20</b> is primarily due to selectively inhibiting essential <i>Ca</i>Mrt4-rRNA interaction by conjointly covalent engaging C96&amp;C189 on <i>Ca</i>Mrt4 but inactive for <i>Hu</i>Mrt4-rRNA interaction, thereby disrupting fungal ribosomal assembly. Therapeutic efficacy of <b>20</b> in both <i>Galleria mellonella</i> larvae and murine candidiasis models validate this antifungal strategy. Collectively, our studies provide a potential and much needed therapeutic strategy to address the rapidly rising burden of drug-resistant fungal infections.</p>

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Inhibiting Mrt4-rRNA interaction with fumaramidmycin-based derivatives as an antifungal strategy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月4日

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  • Hongxuan Cao,
  • Jie Tu,
  • Jiahui Chen,
  • Bingzhang Chen,
  • Zeyue Huang,
  • Yingjie Wang,
  • Jing Shen,
  • Xiuqi Hu,
  • Jialin Bo,
  • Li Rao,
  • Zheng Liu,
  • Nokwanda P. Makunga,
  • Muhammad Salman Hameed,
  • Chen Su,
  • Jian Wan,
  • Wenqiang Chang,
  • Chunquan Sheng,
  • Yanliang Ren

摘要

The rise of drug resistance and limitations of current antifungal treatments highlight the urgent need for innovative antifungal strategies. Here we present the development of cis-fumaramidmycin-derived analogs inhibiting the interactions of ribosome assembly factor Mrt4 with rRNA to combat fungal infections. Through antifungal screening, we identified a promising lead 20 with strong efficacy against various drug-resistant fungi, including notorious super-fungus Candida auris. A comprehensive approach combining active-and-inactive-based protein profiling (AIBPP), chemical-genetic profiling, and fluorescence polarization revealed that the antifungal activity of 20 is primarily due to selectively inhibiting essential CaMrt4-rRNA interaction by conjointly covalent engaging C96&C189 on CaMrt4 but inactive for HuMrt4-rRNA interaction, thereby disrupting fungal ribosomal assembly. Therapeutic efficacy of 20 in both Galleria mellonella larvae and murine candidiasis models validate this antifungal strategy. Collectively, our studies provide a potential and much needed therapeutic strategy to address the rapidly rising burden of drug-resistant fungal infections.