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

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. Echinocandin B’s clinical potential is limited by its instability and poor solubility, despite its antifungal efficacy. Here, the authors employed combinatorial biosynthesis to construct a structurally diverse echinocandin library, yielding 15 novel derivatives to elucidate the effects of key structural modifications and identifying compound 9 as a promising candidate that exhibits remarkably improved stability and water solubility.