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<p>Echinocandin B, a prominent antifungal natural product, contains multiple hydroxyl groups that are closely associated with its bioactivity and stability. However, its inherent instability and poor aqueous solubility constrain its clinical applications. To address these limitations, a combinatorial biosynthetic strategy was employed to optimize the echinocandin B scaffold. By generating a library of derivatives with distinct hydroxylation patterns and evaluating their antifungal activity and stability, we identified key structural determinants: eliminating the C<sub>5</sub>-OH on the ornithine residue enhances stability, while introducing a C<sub>3</sub>-OH on the homotyrosine residue improves bioactivity. Furthermore, solubility was enhanced through targeted sulfation of the C<sub>4</sub>’-OH on the homotyrosine residue in hydroxylated derivatives. This strategy led to the identification of 15 novel antifungal compounds, notably compound <b>9</b>, which exhibited potent antifungal efficacy along with markedly improved stability and solubility. This study expands the structural diversity of echinocandins and establishes a robust platform for optimizing their physicochemical properties.</p><p></p>

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Construction of a diverse echinocandin library via combinatorial biosynthesis targeting improved physicochemical properties and bioactivity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月31日

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  • Qian Jiang,
  • Yike Wang,
  • Ling Li,
  • Nannan Ren,
  • Jing Peng,
  • Yihui Chen,
  • Zhengran Wang,
  • Nancy P. Keller,
  • Jinzhong Xu,
  • Pinmei Wang

摘要

Echinocandin B, a prominent antifungal natural product, contains multiple hydroxyl groups that are closely associated with its bioactivity and stability. However, its inherent instability and poor aqueous solubility constrain its clinical applications. To address these limitations, a combinatorial biosynthetic strategy was employed to optimize the echinocandin B scaffold. By generating a library of derivatives with distinct hydroxylation patterns and evaluating their antifungal activity and stability, we identified key structural determinants: eliminating the C5-OH on the ornithine residue enhances stability, while introducing a C3-OH on the homotyrosine residue improves bioactivity. Furthermore, solubility was enhanced through targeted sulfation of the C4’-OH on the homotyrosine residue in hydroxylated derivatives. This strategy led to the identification of 15 novel antifungal compounds, notably compound 9, which exhibited potent antifungal efficacy along with markedly improved stability and solubility. This study expands the structural diversity of echinocandins and establishes a robust platform for optimizing their physicochemical properties.