Biosynthesis and genome mining strategies for purine-derived N-nucleoside antibiotics

TL;DR

This paper reviews strategies for discovering new nucleoside antibiotics by analyzing their biosynthesis and genetic patterns.

Contribution

The paper provides a framework for genome mining of purine-derived nucleoside antibiotics using conserved biosynthetic enzymes.

Findings

Purine-derived N-NAs show diverse enzymatic modifications leading to varied pharmacological profiles.

Core enzyme probes can guide genome-based discovery of new nucleoside antibiotics.

Structure–Activity relationships in subclasses like pentostatin and angustmycin can aid rational drug design.

Abstract

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.

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.

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.

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.

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