SIDERITE: Unveiling Hidden Siderophore Diversity in the Chemical Space Through Digital Exploration

Siderophores, a highly diverse family of secondary metabolites, play a crucial role in facilitating the acquisition of the essential iron. However, the current discovery of siderophore relies largely on manual approaches. In this work, we introduced SIDERTE, a digitized siderophore information database containing 822 siderophore records with 649 unique structures. Leveraging this digitalized dataset, we gained a systematic overview of siderophores by their clustering patterns in the chemical space. Building upon this, we developed a ligand-based method for predicting new iron-binding molecules. Applying this method to a commercial library, we experimentally confirmed that 40 out of the 48 molecules predicted as siderophore candidates possessed iron-binding abilities. Expanding our approach to the COCONUT natural product database, we predicted a staggering 3,199 siderophore candidates, showcasing remarkable structure diversity that are largely unexplored. Our study provides a valuable resource for accelerating the discovery of novel iron-binding molecules and advancing our understanding towards siderophores.