Biosynthesis and Genome Mining Strategies for Purine-Derived N-Nucleoside Antibiotics

Yujie WuShiYu WuXiaomin NiuXue YuTuo ChenGuangxiu LiuWei Zhang^*

• Northwest Institute of Eco-Environment and Resources, Chinese Academy of Sciences (CAS), Lanzhou, China

Background: The rise of antibiotic resistance underscores the urgent need for new antimicrobial agents. Nucleoside antibiotics are a structurally diverse class with broad biological activities, among which purine-derived N-nucleoside antibiotics (N-NAs) are of particular interest as their purine-linked frameworks enable diverse enzymatic modifications that yield compounds with distinct pharmacological profiles. Aim of the Review: This review summarizes the bioactivity and biosynthetic logic of representative purine-derived N-NAs, including pentostatin-type compounds, angustmycins, and deazapurine analogues, to provide insights into the genome-based discovery of related natural products. Key Scientific Concepts of the Review: By outlining conserved enzymes and genetic features within known BGCs, we illustrate how core enzyme probes can be used for genome-guided mining of putative clusters. This approach emphasizes both the opportunities and challenges in predicting novel N-NA producers from genomic data. Conclusions: Understanding the biosynthesis and genetic organization of N-NAs not only sheds light on their structural diversity but also provides a framework for genome mining. Specific subclasses such as pentostatin-, angustmycin-, and deazapurine-type compounds exhibit Structure–Activity relationships that could guide the rational design and genome-based discovery of new nucleoside antibiotics.