Inhibitors of nutrient pathways: nature's overlooked antibiotic arsenal.

Abstract

Covering: 1920 to 2026The discovery of antibiotics has historically centered on a core set of physiological targets, including cell wall synthesis, protein translation, and DNA replication. As resistance accelerates and new drug classes remain scarce, there is a growing need to expand into alternative target spaces. One such unexplored area is bacterial nutrient biosynthesis and utilization. Although their therapeutic potential is increasingly recognized, these pathways have yet to be fully integrated into antibiotic discovery pipelines, due in part to longstanding methodological biases, including the widespread use of nutrient-rich screening media that obscure nutrient-targeting activity. In this review, we highlight an overlooked subset of natural product antibiotics that inhibit nutrient metabolism. We consolidate 73 compound classes primarily retrieved from the Dictionary of Natural Products and categorize them into four mechanistic classes: biosynthesis inhibitors, antimetabolites, pro-antimetabolites, and riboswitch inhibitors. Many display whole-cell activity, including against Gram-negative pathogens, and reveal underappreciated structural and functional diversity. Recent advances in defined media design, genome mining, and synthetic biology make these compounds more readily accessible for systematic re-evaluation and optimization. Nutrient pathway inhibitors offer a source of novel antibiotic scaffolds and a foundation for therapeutic strategies such as drug potentiation and resistance reversal. Reintegrating these compounds into discovery pipelines can help diversify antibacterial options and address pressing resistance challenges.