Advances in natural product discovery: strategies, technologies, and insights

Natural products (NPs) and their analogues have long underpinned therapies in humans, animals, and plants health, yet, discovering truly novel scaffolds remains a formidable challenge, even with the enormous diversity offered. Over the last two decades, breakthroughs in bioinformatics, cheminformatics, advanced analytical methods, synthetic biology toolkits, and optimized microbial culture have surmounted many of the bottlenecks that stalled NP research in the 1990s and 2000s. Researchers now deploy innovative extraction and purification protocols alongside high-throughput dereplication tools to fish trace metabolites out of complex matrices. These combined approaches not only enable the discovery and rigorous characterization of biosynthesized metabolites, bio-transformed analogues and new chemical entities but also allow precise tuning of biosynthetic gene clusters (BGCs) and culture conditions- modulation and optimization, dramatically improving yield, scalability, and cost-efficiency. Several of these newly unearthed compounds exhibit unique bioactivities that directly inspire drug-development programs against metabolic disorders, cancer drug resistance, and infectious diseases. In this review, we present an up-to-date, concise roadmap of natural product discovery (NPD), majorly covering strategies for awakening silent BGCs, genome mining, and late-stage diversification systems, and we discuss the current limitations and perspectives of rational NPD.